Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches
Open accessAbstract
The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.
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CAG expansion in HD is dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2.
“Notably, CAG expansion has been found to be dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2, whose detection of oxidized or mismatched bases in these repetitive elements could potentially elicit erroneous repair, leading to CAG expansion (Kovtun et al, 2007; Bettencourt et al, 2016; Pinto et al, 2013; Manley et al, 1999; Lee et al, 2017, 1).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Pinto et al, 2013
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Cites
A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610 · cited 1× · see citing works
“Relative mRNA expression levels were determined using the 2 2 DD Cp method [94] by normalization to the housekeeping gene Actb (Mm00607939_s1).”
MethodFast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576 · cited 1× · see citing works
“Protein sequence alignment was performed using Clustal Omega [96] and visualized in Jalview [97] with BLOSUM62 color scheme: white, residue does not match the consensus residue at that position; light blue, residue does not match the consensus residue but the two residues have a positive BLOSUM62 score; dark blue, res…”
MethodA method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · cited 1× · see citing works
“[48] predicting E390D, G404V and M528I to be ‘‘benign’’, but”
Jalview Version 2—a multiple sequence alignment editor and analysis workbench
Waterhouse, A. M., Procter, J. B., Martin, D. M. A., Clamp, M. E., & Barton, G. J. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp033 · Cited by 10,011 · see citing works
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Lander, E. S., Green, P., Abrahamson, J., Barlow, A., Daly, M. J., Lincoln, S. E., & Newberg, L. A. (1987) · Genomics · doi:10.1016/0888-7543(87)90010-3 · Cited by 6,657 · cited 1× · see citing works
“Linkage analysis was performed using Mapmaker/QTL [81–84], with striatal HTT CAG instability indices as quantitative traits.”
MethodSelf-citationMapping mendelian factors underlying quantitative traits using RFLP linkage maps.
Lander, E. S., & Botstein, D. (1989) · Genetics · doi:10.1093/genetics/121.1.185 · Cited by 5,236 · see citing works
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Lander, E. S., & Kruglyak, L. (1995) · Nature Genetics · doi:10.1038/ng1195-241 · Cited by 5,196 · cited 3× · see citing works
“A threshold LOD-score of 4.3 was considered for the identification of significant QTLs [85].”
BackgroundInfluentialShah, M. A., Datson, N. A., Srinidhi, L., Stanton, V. P., MacDonald, M. E., Allard, M. W., Youngman, S., Am, F., Mott, R., Draths, K., et al. (1993) · Cell · Cited by 3,055 · see citing works
Mouse genomic variation and its effect on phenotypes and gene regulation.
Keane, T. M., Goodstadt, L., Danecek, P., White, M. A., Wong, K., Yalcin, B., Heger, A., Agam, A., Slater, G., Goodson, M., et al. (2011) · Nature · doi:10.1038/nature10413 · Cited by 1,580 · cited 10× · see citing works
“(B) Distribution of polymorphisms identified between B6, 129, FVB and DBA mouse strains at a 16 kb genomic region containing the Trex1 and Atrip genes (chr9:109,057,932–109,074,124; GRCm38/ mm10) using information from the Mouse Genomes Project [44,45].”
BackgroundMethodInfluentialPaterson, A. H., Lander, E. S., Hewitt, J. D., Peterson, S., Lincoln, S. E., & Tanksley, S. D. (1988) · Nature · doi:10.1038/335721a0 · Cited by 1,520 · cited 1× · see citing works
“Linkage analysis was performed using Mapmaker/QTL [81–84], with striatal HTT CAG instability indices as quantitative traits.”
MethodKunkel, T. A., & Erie, D. A. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133243 · Cited by 1,372 · cited 2× · see citing works
“It is known that MLH1 is an obligate subunit of three MutL complexes: MutL a (MLH1-PMS2), MutL b (MLH1-PMS1) and MutL c (MLH1–MLH3) (reviewed in [37,38]).”
BackgroundReorganizing the protein space at the Universal Protein Resource (UniProt)
The UniProt Consortium (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr981 · Cited by 1,223 · cited 1× · see citing works
“Note that none of these variants has been identified in human MLH1 [47].”
BackgroundTrinucleotide repeat length instability and age of onset in Huntington's disease
Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., et al. (1993) · Nature Genetics · doi:10.1038/ng0893-387 · Cited by 1,089 · cited 1× · see citing works
“The expanded HTT CAG repeat is highly unstable both in the germline and in somatic tissues [6–13].”
BackgroundA transposase strategy for creating libraries of circularly permuted proteins
Mehta, M., Liu, S., & Silberg, J. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks060 · Cited by 1,042 · see citing works
ATR and ATRIP: Partners in Checkpoint Signaling
Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001) · Science · doi:10.1126/science.1065521 · Cited by 985 · cited 1× · see citing works
“Two additional genes, Trex1 and Atrip, located within the 2 LOD drop-off interval, are involved in DNA repair [52,53].”
BackgroundNuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology
Gutekunst, C.-A., Li, S.-H., Yi, H., Mulroy, J. S., Kuemmerle, S., Jones, R., Rye, D., Ferrante, R. J., Hersch, S. M., & Li, X.-J. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-07-02522.1999 · Cited by 914 · cited 3× · see citing works
“Immunostaining was carried out with polyclonal anti-huntingtin antibody EM48 [87] on 7 mm paraffin-embedded coronal sections of periodate-lysine-paraformaldehyde (PLP)-perfused mouse brains, as previously described [17].”
MethodInfluentialKlungland, A., & Lindahl, T. (1997) · The EMBO Journal · doi:10.1093/emboj/16.11.3341 · Cited by 789 · cited 1× · see citing works
“Two additional genes, Trex1 and Atrip, located within the 2 LOD drop-off interval, are involved in DNA repair [52,53].”
BackgroundThe U.S.–Venezuela Collaborative Research Project*, & Wexler, N. S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308679101 · Cited by 761 · cited 1× · see citing works
“evidence supporting the contribution of genetic factors [3,4].”
BackgroundEndonucleolytic Function of MutLα in Human Mismatch Repair
Kadyrov, F. A., Dzantiev, L., Constantin, N., & Modrich, P. L. (2006) · Cell · doi:10.1016/j.cell.2006.05.039 · Cited by 626 · cited 2× · see citing works
“activity of PMS2 [62], which, interestingly, is activated by extrahelical CAG/CTG repeats in vitro [63].”
BackgroundDominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells
Trettel, F. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.19.2799 · Cited by 614 · cited 1× · see citing works
“type mouse immortalized striatal cells [95].”
Meiotic Pachytene Arrest in MLH1-Deficient Mice
Edelmann, W., Cohen, P. E., Kane, M., Lau, K., Morrow, B. E., Bennett, S. E., Umar, A., Kunkel, T. A., Cattoretti, G., Chaganti, R. S. K., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81312-4 · Cited by 546 · cited 14× · see citing works
“Hdh and Mlh1 null mice (B6) [36] Figure 1.”
BackgroundMethodInfluentialSelf-citationStrategies for mapping and cloning quantitative trait genes in rodents
Jonathan Flint, C., Valdar, W. S. J., Shifman, S., & Mott, R. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1576 · Cited by 497 · cited 1× · see citing works
“While these data were consistent with a dominant B6 modifier(s) we established an F2 intercross in order to search in an unbiased manner for both dominant and recessive modifier loci [34].”
BackgroundAccuracy of mapping quantitative trait loci in autogamous species
van Ooijen, J. W. (1992) · Theoretical and Applied Genetics · doi:10.1007/bf00227388 · Cited by 473 · cited 3× · see citing works
“determined by using the 2-LOD-dropoff method [35,86],”
MethodWheeler, V. C. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.4.503 · Cited by 471 · cited 1× · see citing works
“which is both dominant and CAG length-dependent [16], is a”
BackgroundSelf-citationMutations Associated with HNPCC Predisposition — Update of ICG‐HNPCC/INSiGHT Mutation Database
Peltomäki, P., & Vasen, H. F. A. (2004) · Disease Markers · doi:10.1155/2004/305058 · Cited by 442 · cited 2× · see citing works
“Conversely, MSH6 and PMS2 play prominent roles in classical MMR [72–74].”
BackgroundSomatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm
Telenius, H., Kremer, B., Goldberg, Y. P., Theilmann, J., Andrew, S. E., Zeisler, J., Adam, S., Greenberg, C., Ives, E. J., Clarke, L. A., et al. (1994) · Nature Genetics · doi:10.1038/ng0494-409 · Cited by 439 · cited 1× · see citing works
“The expanded HTT CAG repeat is highly unstable both in the germline and in somatic tissues [6–13].”
BackgroundOGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., & McMurray, C. T. (2007) · Nature · doi:10.1038/nature05778 · Cited by 433 · cited 1× · see citing works
“Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76–78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated. doi:10.1371/journal.pgen.1003930.g011 was…”
BackgroundInfluentialMANLEY, K. M., Shirley, T. L., Flaherty, L. A., & Messer, A. C. (1999) · Nature Genetics · doi:10.1038/70598 · Cited by 415 · cited 2× · see citing works
“While the effects of MMR proteins on instability can vary according to the repeat sequence and its context [21–28], it is notable that Msh2 and Msh3 enhance CAG/ CTG expansion both in HD and DM1 mouse models [18–23, 25– 27 ], An alternative approach for identifying modifiers in the mouse is to take…”
BackgroundResultLi, G., & Modrich, P. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.6.1950 · Cited by 409 · cited 2× · see citing works
“In essence, repair of single base mismatch (G-T) substrate containing a 5 9 nick was assessed using HeLa or MutL a -deficient HCT116 [89] nuclear protein extracts (100 ng) complemented with equal amounts of purified MutL a protein complexes: hMLH1.”
MethodSelf-citationLength-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse
Wheeler, V. C. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.1.115 · Cited by 395 · cited 1× · see citing works
“Hdh mice [15] for at least 10 generations.”
BackgroundSelf-citationKennedy, L. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg352 · Cited by 384 · cited 2× · see citing works
“instability is expansion-biased and prevalent in brain regions that are most susceptible to neurodegeneration [7].”
BackgroundCAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
Lee, J.-H., Ramos, E. M., Lee, J.-H., Gillis, T., Mysore, J. S., Hayden, M. R., Warby, S. C., Morrison, P., NANCE, M. A., Ross, C. A., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e318249f683 · Cited by 383 · cited 1× · see citing works
“The length of the longer CAG repeat tract is the primary determinant of age of disease onset [2].”
BackgroundSelf-citationReconstitution of 5′-Directed Human Mismatch Repair in a Purified System
Zhang, Y., Yuan, F., Presnell, S. R., Tian, K., Gao, Y., Tomkinson, A. E., Gu, L., & Li, G. (2005) · Cell · doi:10.1016/j.cell.2005.06.027 · Cited by 380 · cited 6× · see citing works
“The wild-type human MLH1 cDNA (hMLH1-WT) baculovirus expression vector [49] was used to generate a mutant hMLH1 cDNA construct carrying the 129-like Ile residue at aa192 (hMLH1-F192I) by site directed mutagenesis.”
BackgroundMethodInfluentialSelf-citationMeiotic arrest and aneuploidy in MLH3-deficient mice
Lipkin, S. M., Møens, P. B., Wang, V., Lenzi, M. L., Shanmugarajah, D., Gilgeous, A., Thomas, J. W., Cheng, J., Touchman, J. W., Green, E. D., et al. (2002) · Nature Genetics · doi:10.1038/ng931 · Cited by 379 · cited 9× · see citing works
“Hdh with Mlh3 null mice (B6) [39] and quantified HTT CAG repeat size distributions in the tail, striatum and liver of 24-week-old B6.”
BackgroundMethodInfluentialSelf-citationSwami, M., Hendricks, A. E., Gillis, T., Massood, T., Mysore, J. S., Myers, R. H., & Wheeler, V. C. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp242 · Cited by 330 · cited 3× · see citing works
“expansion that occurs between HD patients [9,11].”
BackgroundResultSelf-citationInstability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation
Mangiarini, L., Sathasivam, K., Mahal, A., Mott, R., Seller, M. J., & Bates, G. P. (1997) · Nature Genetics · doi:10.1038/ng0297-197 · Cited by 318 · cited 1× · see citing works
“was determined using a human-specific PCR assay that amplifies the HTT CAG repeat from the knock-in allele but does not amplify the mouse sequence [79].”
MethodSugawara, N., Pâques, F., Colaiácovo, M. P., & Haber, J. E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.17.9214 · Cited by 311 · cited 1× · see citing works
“mediated expansion arising via other pathways that are MutLindependent, such as single strand annealing [23,61].”
Backgroundvan den Broek, W. J., Nelen, M., Wansink, D. G., Coerwinkel, M., Riele, H. T., Groenen, P., & Wieringa, B. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.2.191 · Cited by 309 · see citing works
Sequence-based characterization of structural variation in the mouse genome
Yalcin, B., Wong, K., Agam, A., Goodson, M., Keane, T. M., Gan, X., Nellåker, C., Goodstadt, L., Nicod, J., Bhomra, A., et al. (2011) · Nature · doi:10.1038/nature10432 · Cited by 301 · see citing works
Flores‐Rozas, H., & Kolodner, R. D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12404 · Cited by 280 · cited 1× · see citing works
“Outside of its role in meiotic recombination [39], MutLc appears to function predominantly with MutSb both in somatic and germ cells [40,41].”
BackgroundDragileva, E., Hendricks, A. E., Teed, A. M., Gillis, T., Lopez, E., Friedberg, E. C., Kucherlapati, R., Edelmann, W., Lunetta, K. L., MacDonald, M. E., et al. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.09.014 · Cited by 247 · cited 13× · see citing works
“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundMethodInfluentialSelf-citationMismatch repair gene Msh2 modifies the timing of early disease in HdhQ111 striatum
Wheeler, V. C. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg056 · Cited by 232 · cited 10× · see citing works
“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundInfluentialSelf-citationDNA instability in postmitotic neurons
Gonitel, R., Moffitt, H., Sathasivam, K., Woodman, B., Detloff, P., Faull, R., & Bates, G. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0800048105 · Cited by 225 · cited 1× · see citing works
“The findings that MMR proteins are required for, rather than protect against somatic CAG/CTG instability, that repeat expansions occur in postmitotic cells [10,33,71] and that expansions in neurons require MSH2 [20], suggest that CAG/CTG repeat expansion may arise via a noncanonical MMR pathway(s).”
Background(CAG)n-hairpin DNA binds to Msh2–Msh3 and changes properties of mismatch recognition
Owen, B. A. L., Yang, Z., Lai, M., Gajek, M., Badger, J. D., Hayes, J. J., Edelmann, W., Kucherlapati, R., Wilson, T., & McMurray, C. T. (2005) · Nature Structural & Molecular Biology · doi:10.1038/nsmb965 · Cited by 222 · cited 4× · see citing works
“role for proteins downstream of MutL complexes in somatic CAG/CTG expansion has not been demonstrated to date, the requirements for MLH1 and MLH3 indicate that the generation of somatic Hdh CAG expansions requires active engagement of the MMR machinery, in contrast to a model whereby expansions occur due to the inabil…”
BackgroundInfluentialShelbourne, P., Keller-McGandy, C. E., Bi, W. L., Yoon, S., Dubeau, L., Veitch, N., Vonsattel, J. P., Wexler, N. S., Arnheim, N., & Augood, S. J. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm054 · Cited by 219 · cited 1× · see citing works
“The findings that MMR proteins are required for, rather than protect against somatic CAG/CTG instability, that repeat expansions occur in postmitotic cells [10,33,71] and that expansions in neurons require MSH2 [20], suggest that CAG/CTG repeat expansion may arise via a noncanonical MMR pathway(s).”
BackgroundCTG repeat instability and size variation timing in DNA repair‐deficient mice
Savouret, C., Brisson, E., Essers, J., Kanaar, R., Pastink, A., Riele, H. T., Junien, C., & Gourdon, G. (2003) · EMBO Journal · doi:10.1093/emboj/cdg202 · Cited by 215 · cited 2× · see citing works
“mediated expansion arising via other pathways that are MutLindependent, such as single strand annealing [23,61].”
BackgroundFunctional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system
Trojan, J., Zeuzem, S., Randolph, A. E., Hemmerle, C., Brieger, A., Raedle, J., Plotz, G., Jiricny, J., & Marra, G. (2002) · Gastroenterology · doi:10.1053/gast.2002.30296 · Cited by 213 · see citing works
Gomes-Pereira, M. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh186 · Cited by 201 · cited 5× · see citing works
“However, MSH6 is either unnecessary for, or plays a very minimal role in mediating somatic CAG/CTG expansions [19,22,25], and knockout of Pms2 had a moderate effect of CTG expansion in DM1 mice [24], implicating a role for different MLH1 partners.”
BackgroundResultInfluentialHuntingtin facilitates polycomb repressive complex 2
Seong, I. S., Woda, J. M., Song, J., Lloret, A., Abeyrathne, P. D., Woo, C. J., Gregory, G. C., Lee, J., Wheeler, V. C., Walz, T., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp524 · Cited by 188 · cited 1× · see citing works
“Full-length Mlh1 cDNAs were amplified by PCR (for primers used see Table S2) using Phusion High-Fidelity DNA polymerase (New England Biolabs), and were subsequently cloned between the unique NcoI and XhoI sites of a modified pFastBac1 baculovirus expression vector [88], so that the resulting recombinant MLH1 proteins…”
MethodSelf-citationThe FANCJ/MutLα interaction is required for correction of the cross‐link response in FA‐J cells
Peng, M., Litman, R., Xie, J., Sharma, S., Brosh, R. M., & Cantor, S. B. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601754 · Cited by 181 · see citing works
MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice
Tomé, S., MANLEY, K. M., Simard, J. P., Clark, G. W., Slean, M. M., Swami, M., Shelbourne, P., Tillier, E. R. M., Monckton, D. G., Messer, A. C., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003280 · Cited by 171 · cited 7× · see citing works
“Interestingly, Msh3 gene variants were recently found to correlate with HTT CAG instability in some strains of R6/1 transgenic mice [29].”
BackgroundInfluentialSelf-citationFoiry, L., Dong, L., Savouret, C., Hubert, L., Riele, H. T., Junien, C., & Gourdon, G. (2006) · Human Genetics · doi:10.1007/s00439-006-0164-7 · Cited by 151 · cited 20× · see citing works
“However, at least for the B6N and 129S2 strains in which we have performed genome-wide QTL mapping, it is clear from the genetic data that any polymorphisms in the Msh3 gene do not play a significant role in driving these strain-specific differences in somatic expansion of the Hdh Q111 CAG repeat (Figure 2B).”
BackgroundInfluentialA Genome Scan for Modifiers of Age at Onset in Huntington Disease: The HD MAPS Study
Li, J., Hayden, M. R., Almqvist, E. W., Brinkman, R. R., Dürr, A., Dodé, C., Morrison, P. J., Suchowersky, O., Ross, C. A., Margolis, R. L., et al. (2003) · The American Journal of Human Genetics · doi:10.1086/378133 · Cited by 149 · cited 1× · see citing works
“evidence supporting the contribution of genetic factors [3,4].”
BackgroundSelf-citationA novel approach to investigate tissue-specific trinucleotide repeat instability
Lee, J., Zhang, J., Su, A. I., Walker, J. R., Wiltshire, T., Kang, K., Dragileva, E., Gillis, T., Lopez, E., Boily, M.-J., et al. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-29 · Cited by 148 · cited 2× · see citing works
“Hdh striata using a previously described method [32].”
MethodSelf-citationGoula, A.-V., Berquist, B. R., Wilson, D. M., Wheeler, V. C., Trottier, Y., & Mérienne, K. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000749 · Cited by 145 · cited 1× · see citing works
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultSelf-citationNoncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
Peña-Dı́az, J., Bregenhorn, S., Ghodgaonkar, M. M., Follonier, C., Borán, M. S., Castor, D., Lopes, M., Sartori, A. A., & Jiricny, J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.07.006 · Cited by 145 · cited 1× · see citing works
“promutagenic noncanonical MMR pathway has been described, which occurs in multiple cell types, is independent of DNA replication and is activated by DNA lesions rather than mismatches [70].”
BackgroundHuman MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases
Pearson, C. E. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.7.1117 · Cited by 144 · cited 1× · see citing works
“CAGNCTG repeat structures are initially recognized by the MutSb (MSH2-MSH3) complex [25,98].”
BackgroundSelf-citationFunctional Analysis of Human MLH1 Variants Using Yeast and In vitro Mismatch Repair Assays
Takahashi, M., Shimodaira, H., Andreutti-Zaugg, C., Iggo, R. D., Kolodner, R. D., & Ishioka, C. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3509 · Cited by 139 · cited 1× · see citing works
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutL a complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
ResultEdelbrock, M. A., Saravanan, K., & Williams, K. J. (2013) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2012.12.008 · Cited by 139 · cited 1× · see citing works
“However, there is increasing evidence that MMR proteins play various roles in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundFactors associated with HD CAG repeat instability in Huntington disease
Wheeler, V. C., Persichetti, F., McNeil, S. M., Mysore, J. S., Mysore, S. S., MacDonald, M. E., Myers, R. H., Gusella, J. F., & Wexler, N. S. (2007) · Journal of Medical Genetics · doi:10.1136/jmg.2007.050930 · Cited by 139 · cited 1× · see citing works
“The expanded HTT CAG repeat is highly unstable both in the germline and in somatic tissues [6–13].”
BackgroundSelf-citationNoncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
Peña-Dı́az, J., Bregenhorn, S., Ghodgaonkar, M. M., Follonier, C., Borán, M. S., Castor, D., Lopes, M., Sartori, A. A., & Jiricny, J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.026 · Cited by 133 · see citing works
Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair
Cannavò, E., Marra, G., Sabates–Bellver, J., Menigatti, M., Lipkin, S. M., Fischer, F., Ćejka, P., & Jiricny, J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2528 · Cited by 125 · cited 4× · see citing works
“As shown previously [50], complementation of MLH1-and PMS2-deficient HEK293T cells with wild-type human MutL a restored repair activity (Figure 8A).”
MethodInfluentialMouse models for human DNA mismatch-repair gene defects
Wei, K., Kucherlapati, R., & Edelmann, W. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02359-6 · Cited by 124 · cited 2× · see citing works
“Conversely, MSH6 and PMS2 play prominent roles in classical MMR [72–74].”
BackgroundHuntington's disease: the case for genetic modifiers
Gusella, J. F., & MacDonald, M. E. (2009) · Genome Medicine · doi:10.1186/gm80 · Cited by 120 · cited 1× · see citing works
“pursued via a number of candidate and global genetic approaches [5].”
BackgroundCoordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion
Liu, Y., Prasad, R., Beard, W. A., Hou, E. W., Horton, J. K., McMurray, C. T., & Wilson, S. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.050286 · Cited by 115 · cited 1× · see citing works
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultMammalian mismatch repair: error-free or error-prone?
Peña-Dı́az, J., & Jiricny, J. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.03.001 · Cited by 109 · see citing works
MSH2 ATPase Domain Mutation Affects CTG•CAG Repeat Instability in Transgenic Mice
Tomé, S., Holt, I., Edelmann, W., Morris, G. E., Münnich, A., Pearson, C. E., & Gourdon, G. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000482 · Cited by 103 · see citing works
Self-citationFine mapping in 94 inbred mouse strains using a high-density haplotype resource
Kirby, A., Kang, H. M., Wade, C. M., Cotsapas, C., Kostem, E., Han, B., Furlotte, N., Kang, E. Y., Rivas, M., Bogue, M. A., et al. (2010) · Genetics · doi:10.1534/genetics.110.115014 · Cited by 102 · cited 5× · see citing works
“In an attempt to primarily enhance resolution at this QTL, but also to specifically investigate the Mlh1 gene, we genotyped the F2 animals for 10 additional markers distributed across the QTL region, including two markers located within the Mlh1 gene (Figure S3 and Table S1).”
MethodInfluentialSelf-citationRaamsdonk, J. M. V., Metzler, M., Slow, E., Pearson, J., Schwab, C., Carroll, J. B., Graham, R. K., Leavitt, B. R., & Hayden, M. R. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.010 · Cited by 101 · see citing works
Chen, P., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S., Yang, K., Arnheim, N., Liskay, R. M., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0742 · Cited by 100 · see citing works
Panigrahi, G. B., Slean, M. M., Simard, J. P., Gileadi, O., & Pearson, C. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909087107 · Cited by 93 · cited 2× · see citing works
“We then tested the ability of B6 and 129 MLH1 proteins to repair a single CTG slip-out (CAG)47N(CTG)48 [50,51], a potential intermediate in the expansion process, as requirements for processing of slipped-DNAs formed by trinucleotide repeats may more closely resemble those that ultimately result in CAG expansion in mi…”
BackgroundMethodSelf-citationLloret, A., Dragileva, E., Teed, A. M., Espinola, J. A., Fossale, E., Gillis, T., Lopez, E., Myers, R. H., MacDonald, M. E., & Wheeler, V. C. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl125 · Cited by 92 · cited 9× · see citing works
“In concordance with our previous qualitative assessment [17], the quantification of instability in striatum and”
BackgroundResultInfluentialSelf-citationKovalenko, M. V., Dragileva, E., Claire, J. S., Gillis, T., Guide, J. R., New, J., Dong, H., Kucherlapati, R., Kucherlapati, M. H., Ehrlich, M. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044273 · Cited by 88 · cited 6× · see citing works
“Importantly, we find that the MutL c components, MLH1 and MLH3, are as critical to somatic Hdh Q111 CAG expansion as the MutS b components MSH2 and MSH3 [18,19], suggesting that MutL c and MutS b are involved in the same pathway that promotes CAG/CTG expansion.”
BackgroundInfluentialSelf-citationLee, J., Pinto, R. M., Gillis, T., Claire, J. S., & Wheeler, V. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023647 · Cited by 87 · cited 3× · see citing works
“Hdh mice [33], we also quantified instability indices in B6.”
BackgroundMethodSelf-citationFunctional Characterization of Pathogenic Human MSH2 Missense Mutations in Saccharomyces cerevisiae
Gammie, A. E., Erdeniz, N., Beaver, J. A., Devlin, B., Nanji, A., & Rose, M. D. (2007) · Genetics · doi:10.1534/genetics.107.071084 · Cited by 87 · cited 1× · see citing works
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutL a complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
ResultA Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases
Kaplan, S., Itzkovitz, S., & Shapiro, E. Y. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030235 · Cited by 81 · cited 1× · see citing works
“Mathematical modeling has suggested a mechanism by which somatic expansion beyond a threshold repeat length is required for clinical onset [14].”
BackgroundNovel and diverse functions of the DNA mismatch repair family in mammalian meiosis and recombination
Kolas, N. K., & Cohen, P. E. (2004) · Cytogenetic and Genome Research · doi:10.1159/000080600 · Cited by 77 · cited 1× · see citing works
“in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundSelf-citationPluciennik, A., Burdett, V., Baitinger, C., Iyer, R. R., Shi, K. X., & Modrich, P. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311325110 · Cited by 76 · cited 1× · see citing works
“activity of PMS2 [62], which, interestingly, is activated by extrahelical CAG/CTG repeats in vitro [63].”
BackgroundMøllersen, L., Rowe, A. D., Illuzzi, J. L., Hildrestrand, G. A., Gerhold, K. J., Tveterås, L., Bjølgerud, A., Wilson, D. M., Bjørås, M., & Klungland, A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds337 · Cited by 74 · cited 1× · see citing works
“Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76–78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated. doi:10.1371/journal.pgen.1003930.g011 was…”
BackgroundInfluentialHall, M. C., Shcherbakova, P. V., & Kunkel, T. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106120200 · Cited by 73 · cited 2× · see citing works
“though outside conserved ATP binding motifs [46]; E390D and”
BackgroundHubert, L., Lin, Y., Dion, V., & Wilson, J. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr421 · Cited by 70 · cited 2× · see citing works
“Other members of alternative DNA repair pathways, namely OGG1, XPA and NEIL1 have been directly implicated in CAG/CTG somatic instability in mice [76–78], however, how these proteins intersect with MMR protein-dependent pathways has yet to be demonstrated.”
BackgroundSomatic expansion of the (CAG) n repeat in Huntington disease brains
de Rooij, K. E., Gans, P. A. M. D. K., Roos, R. A. C., van Ommen, G. B., & den Dunnen, J. T. (1995) · Human Genetics · doi:10.1007/bf00225192 · Cited by 68 · see citing works
Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops
Lang, W. H., Coats, J. E., Majka, J., Hura, G. L., Lin, Y., Rasnik, I., & McMurray, C. T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105461108 · Cited by 67 · cited 1× · see citing works
“role for proteins downstream of MutL complexes in somatic CAG/CTG expansion has not been demonstrated to date, the requirements for MLH1 and MLH3 indicate that the generation of somatic Hdh CAG expansions requires active engagement of the MMR machinery, in contrast to a model whereby expansions occur due to the inabil…”
BackgroundLander, E. S., Green, P., Abrahamson, J., Barlow, A., Daly, M. J., Lincoln, S. E., & Newberg, L. A. (2009) · Genomics · doi:10.1016/j.ygeno.2008.12.003 · Cited by 67 · see citing works
Self-citationEzzatizadeh, V., Pinto, R. M., Sandi, C., Sandi, M., Al‐Mahdawi, S., Riele, H. T., & Pook, M. A. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.01.002 · Cited by 59 · cited 1× · see citing works
“Given evidence suggesting a role for MMR pathways in both somatic and intergenerational repeat instability [18,23,59], it is plausible that genetic variation at the Mlh1 locus also underlies the difference in intergenerational instability between the two strains.”
BackgroundSelf-citationPms2 Suppresses Large Expansions of the (GAA·TTC)n Sequence in Neuronal Tissues
Bourn, R. L., Biase, I. D., Pinto, R. M., Sandi, C., Al‐Mahdawi, S., Pook, M. A., & Bidichandani, S. I. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047085 · Cited by 59 · cited 2× · see citing works
“While the effects of MMR proteins on instability can vary according to the repeat sequence and its context [21–28], it is notable that Msh2 and Msh3 enhance CAG/ CTG expansion both in HD and DM1 mouse models [18–23, 25– 27 ], An alternative approach for identifying modifiers in the mouse is to take…”
BackgroundResultSelf-citationSlean, M. M., Panigrahi, G. B., Ranum, L. P. W., & Pearson, C. E. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.03.014 · Cited by 53 · cited 1× · see citing works
“However, there is increasing evidence that MMR proteins play various roles in the absence of DNA replication and participate in a variety of other pathways, distinct from MMR [64–69].”
BackgroundSelf-citationVeitch, N., Ennis, M., McAbney, J. P., Shelbourne, P., & Monckton, D. G. (2007) · DNA repair · doi:10.1016/j.dnarep.2007.01.002 · Cited by 52 · cited 1× · see citing works
“expansion that occurs between HD patients [9,11].”
Lin, Y., & Wilson, J. H. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.04.024 · Cited by 51 · cited 1× · see citing works
“MLH1 has been found to play a role in CAG repeat instability in a selectable cell-based system [58].”
BackgroundLópez, A., Tomkinson, A. E., & Pearson, C. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.034405 · Cited by 43 · cited 1× · see citing works
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
ResultSelf-citationGoula, A.-V., Pearson, C. E., Della-Maria, J., Trottier, Y., Tomkinson, A. E., Wilson, D. M., & Mérienne, K. (2012) · Biochemistry · doi:10.1021/bi300410d · Cited by 41 · see citing works
Self-citationPanigrahi, G. B., Slean, M. M., Simard, J. P., & Pearson, C. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.420398 · Cited by 41 · cited 7× · see citing works
“Repair of a single trinucleotide repeat slip-out by MLH1 was investigated as previously described [50].”
BackgroundMethodInfluentialSelf-citationTomé, S., Simard, J. P., Slean, M. M., Holt, I., Morris, G. E., Wojciechowicz, K., Riele, H. T., & Pearson, C. E. (2012) · DNA repair · doi:10.1016/j.dnarep.2012.10.006 · Cited by 37 · cited 2× · see citing works
“It is worth noting that a number of other studies support a role for the levels or stoichiometries of DNA repair proteins in trinucleotide repeat instability [43,54–57].”
BackgroundResultSelf-citationEvidence that hMLH3 functions primarily in meiosis and in hMSH2-hMSH3 mismatch repair
Charbonneau, N., Amunugama, R., Schmütte, C., Yoder, K. E., & Fishel, R. A. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.14.8886 · Cited by 30 · cited 5× · see citing works
“in interaction with MSH3, EXOI, MLH3, PMS1 and PMS2 [41]”
BackgroundInfluentialMutL: conducting the cell's response to mismatched and misaligned DNA
Polosina, Y. Y., & Cupples, C. G. (2009) · BioEssays · doi:10.1002/bies.200900089 · Cited by 28 · cited 2× · see citing works
“enzymatic processing of the DNA mismatch [37,38].”
BackgroundPlaschke, J., Preußler, M., Ziegler, A., & Schackert, H. K. (2012) · International Journal of Colorectal Disease · doi:10.1007/s00384-011-1408-0 · Cited by 23 · cited 1× · see citing works
“Withregard to potential mechanisms of CAG expansion it is of interest that MSH3 and MLH3 appear to play relatively minor roles in classical MMR inasmuch as Msh3 and Mlh3 deficiencies result in weak mutator phenotypes and relatively low cancer predisposition phenotypes [42,72–75].”
BackgroundPolosina, Y. Y., & Cupples, C. G. (2010) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2010.07.002 · Cited by 21 · see citing works
Cowin, R.-M., Bui, N., Graham, D. F., Green, J. R., Yuva‐Paylor, L. A., Weiss, A., & Paylor, R. E. (2012) · Mammalian Genome · doi:10.1007/s00335-012-9391-5 · Cited by 12 · cited 1× · see citing works
“ences in trinucleotide repeat instability [17,22,29] and various HD mouse model phenotypes [17,30,31] have been identified.”
BackgroundAldred, P. M. R., & Borts, R. H. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351525 · Cited by 12 · cited 1× · see citing works
“Note that as mMLH1-hPMS2 was functional in this well-established human-based assay, consistent with previous mixed yeast-human MMR assays [90–92], we compared B6 and 129 MLH1 proteins in a mixed mouse-human MutLa complex, avoiding the need to introduce mouse PMS2 as another assay variable.”
Result
Flagged first, then by citations
Research works printed but not linked: 2
- [83]Lincoln SE, Daly MJ, Lander ES (1993) Constructing Genetic Linkage Maps with MAPMAKER/EXP Version 3.0: A Tutorial and Reference Manual. Whitehead Institute for Biomedical Research Technical Report, 3rd edition.
- [84]Lincoln SE, Daly MJ, Lander ES (1993) Mapping Genes Controlling Quantitative Traits Using MAPMAKER/QTL Version 1.1: A Tutorial and Reference Manual. Whitehead Institute for Biomedical Research Technical Report, 2nd edition.
Cited by
Sorted by citations
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641 · see citing works
Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
Lee, J.-M., Wheeler, V. C., Chao, M. J., Vonsattel, J. P. G., Pinto, R. M., Lucente, D., Abu-Elneel, K., Ramos, E. M., Mysore, J. S., Gillis, T., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.003 · Cited by 655 · see citing works
“coli DNA mismatch repair gene mutL), whose mouse homolog, Mlh1, was discovered in a genome-wide genetic screen to modify somatic instability of the CAG repeat and the timing of CAG length-dependent phenotypes in the striatum of genetic HD replica CAG knockin mice (Pinto et al., 2013).”
Self-citationHuntington disease: new insights into molecular pathogenesis and therapeutic opportunities
Tabrizi, S. J., Flower, M. D., Ross, C. A., & Wild, E. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0389-4 · Cited by 544 · see citing works
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset
Lee, J., Correia, K., Loupe, J. M., Kim, K., Barker, D., Hong, E. P., Chao, M. J., Long, J. D., Lucente, D. E., Vonsattel, J. P., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.036 · Cited by 532 · see citing works
“, 1999), and this process is modified by DNA maintenance genes (Dragileva et al., 2009; Pinto et al., 2013; Wheeler et al., 2003).”
Self-citationMolecular mechanisms underlying nucleotide repeat expansion disorders
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00382-6 · Cited by 363 · see citing works
On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability
Khristich, A. N., & Mirkin, S. M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.007678 · Cited by 289 · see citing works
Genetic Background Limits Generalizability of Genotype-Phenotype Relationships
Sittig, L. J., Carbonetto, P. S., Engel, K. A., Krauss, K. S., Barrios-Camacho, C. M., & Palmer, A. A. (2016) · Neuron · doi:10.1016/j.neuron.2016.08.013 · Cited by 247 · see citing works
Efficient prime editing in mouse brain, liver and heart with dual AAVs
Davis, J. R., Banskota, S., Levy, J. M., Newby, G. A., Wang, X., Anzalone, A. V., Nelson, A. T., Chen, P. J., Hennes, A. D., An, M., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-023-01758-z · Cited by 237 · see citing works
“Although the activity of MMR in the mammalian brain is not well understood, Mlh1 is expressed in the mammalian brain 45–47 and may limit prime editing in the central nervous system (CNS).”
Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease
Handsaker, R. E., Kashin, S., Reed, N. M., Tan, S., Lee, W., McDonald, T. M., Morris, K., Kamitaki, N., Mullally, C. D., Morakabati, N. R., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.038 · Cited by 214 · see citing works
Disease-associated repeat instability and mismatch repair
Schmidt, M. H. M., & Pearson, C. E. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.11.008 · Cited by 209 · see citing works
“studies did not reveal an obvious requirement of human MutL (MLH1-MLH3) [27], which contrasts with the apparent absolute requirement of murine MLH3 in HD mice [4].”
BackgroundInfluentialSelf-citationWright, G. E. B., Collins, J. A., Kay, C., McDonald, C. L., Dolzhenko, E., Xia, Q., Bečanović, K., Drögemöller, B. I., Semaka, A., Nguyen, C. M., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.04.007 · Cited by 201 · see citing works
“proaches have been successfully employed to measure huntingtin CAG instability.(21) For these analyses, additional LOI carriers were identified by screening additional family members in the carrier”
MethodData Analytics from Enroll‐ HD , a Global Clinical Research Platform for Huntington's Disease
Landwehrmeyer, G. B., Fitzer‐Attas, C. J., Giuliano, J. D., Gonçalves, N., Anderson, K. E., Cardoso, F., Ferreira, J. J., Mestre, T., Stout, J. C., & Sampaio, C. (2016) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12388 · Cited by 187 · see citing works
“25 With Enroll-HD, we can envision ways to further address this issue, for example, by genotyping individuals or subgroups to dissect these molecular mechanisms.”
MethodRepeat instability during DNA repair: Insights from model systems
Usdin, K., House, N. C. M., & Freudenreich, C. H. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2014.999192 · Cited by 168 · see citing works
“…reflect the effect of sequence context, since cis-acting sequences affect expansion (Brock et al., 1999; Cleary et al., 2002; Libby et al., 2003), or genetic background, since mouse strains differ significantly in the levels of expression of key MMR proteins (Pinto et al., 2013; Tome et al., 2013).”
BackgroundInfluentialMSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Flower, M. D., Lomeikaite, V., Ciosi, M., Cumming, S. A., Morales, F., Lo, K., Moss, D. J. H., Jones, L., Holmans, P., Monckton, D. G., et al. (2019) · Brain · doi:10.1093/brain/awz115 · Cited by 166 · see citing works
“pansion, and their inactivation limits expansion events and improves disease phenotype (van den Broek et al., 2002; Foiry et al., 2006; Dragileva et al., 2009; Pinto et al., 2013; Tome et al., 2013).”
BackgroundFrom Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research
Jiang, A., Handley, R. R., Lehnert, K., & Snell, R. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241613021 · Cited by 168 · see citing works
Mätlik, K., Baffuto, M., Kus, L., Deshmukh, A. L., Davis, D. A., Paul, M. R., Carroll, T. S., Caron, M., Masson, J., Pearson, C. E., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01653-6 · Cited by 151 · see citing works
Self-citationFAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat
Goold, R., Flower, M. D., Moss, D. J. H., Medway, C., Wood‐Kaczmar, A., André, R., Farshim, P. P., Bates, G. P., Holmans, P., Jones, L., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy375 · Cited by 143 · see citing works
“This is pertinent because evidence from mouse models suggests MMR components are required for SI (22,23), and pathway analysis highlights DNA MMR as a strong driver of HD pathogenesis (7).”
BackgroundGenetic modifiers of Huntington's disease
Gusella, J. F., MacDonald, M. E., & Lee, J. (2014) · Movement Disorders · doi:10.1002/mds.26001 · Cited by 150 · see citing works
“By contrast, genetic linkage has been successful in the mouse, using a knock-in model in which an expanded CAG repeat has been inserted in a genetically precise manner into the mouse huntingtin gene.(60) One of the HD-associated phenotypes common to both human and mouse is somatic instability of the CAG repeat in the…”
MethodA slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
Nakamori, M., Panigrahi, G. B., Lanni, S., Gall-Duncan, T., Hayakawa, H., Tanaka, H., Luo, J., Otabe, T., Li, J., Sakata, A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-019-0575-8 · Cited by 147 · see citing works
Self-citationPinto, R. M., Arning, L., Giordano, J. V., Razghandi, P., Andrew, M. A., Gillis, T., Correia, K., Mysore, J. S., Urtubey, D.-M. G., Parwez, C. R., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa139 · Cited by 135 · see citing works
Self-citationDNA triplet repeat expansion and mismatch repair
Iyer, R. R., Pluciennik, A., Napierala, M., & Wells, R. D. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034010 · Cited by 130 · see citing works
“In light of the finding that MLH3 deficiency stabilizes long CAG·CTG repeat tracts in HD transgenic mice (49), future studies addressing the potential involvement of MutLγ in MutSβ-dependent mutagenic repair of triplet repeats are definitely warranted.”
BackgroundMechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
Welch, G., & Tsai, L. (2022) · The EMBO Reports · doi:10.15252/embr.202154217 · Cited by 129 · see citing works
“…proteins such as OGG1, MLH1, and MSH2, whose detection of oxidized or mismatched bases in these repetitive elements could potentially elicit erroneous repair, leading to CAG expansion (Kovtun et al , 2007; Bettencourt et al , 2016; Pinto et al , 2013; Manley et al , 1999; Lee et al , 2017, 1).”
Southwell, A. L., Smith-Dijak, A., Kay, C., Sepers, M. D., Villanueva, E. B., Parsons, M. P., Xie, Y., Anderson, L. M., Felczak, B., Waltl, S., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw212 · Cited by 123 · see citing works
“CAG sizing modified from (17) as in (69) was used to verify that breeders remained within the normal range for the line of around 200.”
MethodA modifier of Huntington's disease onset at the MLH1 locus
Lee, J., Chao, M. J., Harold, D. H., Elneel, K. A., Gillis, T., Holmans, P., Jones, L., Orth, M., Myers, R. H., Kwak, S., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx286 · Cited by 117 · see citing works
Self-citationRoles for mismatch repair family proteins in promoting meiotic crossing over
Manhart, C. M., & Alani, E. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.11.024 · Cited by 111 · see citing works
DNA Mismatch Repair and its Role in Huntington’s Disease
Iyer, R. R., & Pluciennik, A. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200438 · Cited by 112 · see citing works
“373 Missense (LoF?) variant delays onset [103, 155, 159, 162] Attenuates CAG repeat expansion [80, 205] Knockdown attenuates GAA repeat expansions [146] Lynch syndrome [13, 18], CMMR-D [15–17] PMS2 0.”
BackgroundInfluentialHuntington’s Disease Pathogenesis: Two Sequential Components
Hong, E. P., MacDonald, M. E., Wheeler, V. C., Jones, L., Holmans, P., Orth, M., Monckton, D. G., Long, J. D., Kwak, S., Gusella, J. F., et al. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200427 · Cited by 109 · see citing works
Self-citationSu, X. A., & Freudenreich, C. H. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711283114 · Cited by 104 · see citing works
“Our data have potentially significant implications for the Huntington’s disease (HD) process because MutLγ was reported to be important in driving somatic CAG repeat instability in a HD mouse model (63).”
BackgroundThe central role of DNA damage and repair in CAG repeat diseases
Massey, T. H., & Jones, L. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031930 · Cited by 95 · see citing works
“…MMR genes (e.g. Msh2 , Msh3 , Mlh1 or Mlh3 ), or BER genes (e.g. Ogg1 or Neil1 ) can abrogate somatic and/or germline CAG repeat expansion and, in some cases, ameliorate HD-like phenotypes (Budworth et al., 2015; Kovalenko et al., 2012; Pinto et al., 2013; Usdin et al., 2015; Wheeler et al., 2003).”
BackgroundDNA repair in the trinucleotide repeat disorders
Jones, L., Houlden, H., & Tabrizi, S. J. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30350-7 · Cited by 99 · see citing works
DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases
Maiuri, T., Suart, C., Hung, C. L.-K., Graham, K. J., Bazan, C. B., & Truant, R. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00768-7 · Cited by 92 · see citing works
McAllister, B., Donaldson, J., Binda, C. S., Powell, S., Chughtai, U., Edwards, G., Stone, J., Lobanov, S. V., Elliston, L., Schuhmacher, L.-N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01033-5 · Cited by 89 · see citing works
Self-citationModifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
Wheeler, V. C., & Dion, V. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200426 · Cited by 83 · see citing works
“In addition to Msh2 and Msh3, both Mlh1 and Mlh3 are absolutely required for somatic CAG expansion in HttQ111 mice [90], implicating MutL in this process.”
Self-citationLoupe, J. M., Pinto, R. M., Kim, K., Gillis, T., Mysore, J. S., Andrew, M. A., Kovalenko, M. V., Murtha, R., Seong, I., Gusella, J. F., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa196 · Cited by 85 · see citing works
“Previously, the ortholog of MLH1 had been discovered in a linkage study to be a modifier of somatic Htt CAG repeat instability in HD knock-in mice (12) and this finding, together with the observation that HD individuals with the earliest onset had the highest degree of brain CAG repeat expansion (13), implicated somat…”
BackgroundSelf-citationHuman MutLγ, the MLH1–MLH3 heterodimer, is an endonuclease that promotes DNA expansion
Kadyrova, L. Y., Gujar, V. V., Burdett, V., Modrich, P. L., & Kadyrov, F. A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1914718117 · Cited by 84 · see citing works
Morales, F., Vásquez, M., Santamaría, C., Cuenca, P., Corrales, E., & Monckton, D. G. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.01.001 · Cited by 84 · see citing works
Suelves, N., Kirkham-McCarthy, L., Lahue, R. S., & Ginés, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-05125-2 · Cited by 83 · see citing works
DNA methylation study of Huntington’s disease and motor progression in patients and in animal models
Lu, A. T.-H., Narayan, P. J., Grant, M. J., Langfelder, P., Wang, N., Kwak, S., Wilkinson, H. A., Chen, R. Z., Chen, J., Bawden, C. S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18255-5 · Cited by 83 · see citing works
Propensity for somatic expansion increases over the course of life in Huntington disease
Kacher, R., Lejeune, F., Noël, S., Cazeneuve, C., Brice, A., Humbert, S., & Dürr, A. (2021) · eLife · doi:10.7554/elife.64674 · Cited by 83 · see citing works
“Another is to modulate DNA repair activity in HD to retard somatic expansions (Dragileva et al., 2009; Pinto et al., 2013), but this might also run the risk of increasing overall genomic instability.”
BackgroundPinto, R. M., Murtha, R., Azevedo, A., Douglas, C. J., Kovalenko, M. V., Ulloa, J., Crescenti, S., Burch, Z. N., Oliver, E., Kesavan, M., et al. (2025) · Nature Genetics · doi:10.1038/s41588-024-02054-5 · Cited by 78 · see citing works
Self-citationGoold, R., Hamilton, J., Menneteau, T., Flower, M., Bunting, E. L., Aldous, S. G., Porro, A., Vicente, J. R., Allen, N., Wilkinson, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109649 · Cited by 67 · see citing works
“Expansion of CAG repeats occurs in selected somatic and selected meiotic tissues, but the neurodegeneration is primarily due to loss of neurons in the striatum and cortex (MacDonald et al., 1993; Pinto et al., 2013; Rikitake et al., 2020; Tomé et al., 2013).”
BackgroundResultInfluentialDNA repair in the trinucleotide repeat disorders
Jones, L., Houlden, H., & Tabrizi, S. J. (2017) · UCL Discovery (University College London) · Cited by 76 · see citing works
Regulatory mechanisms of incomplete huntingtin mRNA splicing
Neueder, A., Dumas, A. A., Benjamin, A. C., & Bates, G. P. (2018) · Nature Communications · doi:10.1038/s41467-018-06281-3 · Cited by 74 · see citing works
Monckton, D. G. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200429 · Cited by 72 · see citing works
“expansions in HD mice [239], it seems a reason-”
BackgroundInfluentialWang, N., Zhang, S., Langfelder, P., Ramanathan, L., Gao, F., Plascencia, M., Vaca, R., Gu, X., Deng, L., Dionisio, L. E., et al. (2025) · Cell · doi:10.1016/j.cell.2025.01.031 · Cited by 76 · see citing works
R-loops: targets for nuclease cleavage and repeat instability
Freudenreich, C. H. (2018) · Current Genetics · doi:10.1007/s00294-018-0806-z · Cited by 68 · see citing works
“Further analysis showed that expansions were dependent on both Mlh1 and Mlh3, implicating the MutLγ complex as a key driver of somatic CAG expansions in this mouse model (Pinto et al. 2013).”
InfluentialDe novo mutations, genetic mosaicism and human disease
Mohiuddin, M., Kooy, R. F., & Pearson, C. E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.983668 · Cited by 66 · see citing works
“, 2016), and alteration of MMR is sufficient to overturn somatic instability and can moderate toxicity in Huntington disease mice (Kovalenko et al., 2012; Pinto et al., 2013).”
BackgroundSelf-citationA CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease
Aldous, S. G., Smith, E. J., Landles, C., Osborne, G. F., Cañibano-Pico, M., Nita, I. M., Phillips, J. M., Zhang, Y., Jin, B., Hirst, M. B., et al. (2024) · Brain · doi:10.1093/brain/awae063 · Cited by 63 · see citing works
“16 21-23 Mechanistically, it has since been shown that FAN1 nuclease activity is implicated in slowing CAG repeat expansion, 24 that the promotion of somatic CAG instability by FAN1 is blocked in the absence of MLH1 25 and that FAN1 controls mismatch repair assembly via MLH1 to stabilize the CAG…”
InfluentialThe Repeat Expansion Diseases: The dark side of DNA repair
Zhao, X.-N., & Usdin, K. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.04.019 · Cited by 64 · see citing works
O’Reilly, D., Belgrad, J., Ferguson, C. M., Summers, A., Sapp, E., McHugh, C. A., Mathews, E. W., Boudi, A., Buchwald, J. E., Ly, S., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.05.006 · Cited by 60 · see citing works
Structure-forming repeats and their impact on genome stability
Brown, R. E., & Freudenreich, C. H. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.10.006 · Cited by 59 · see citing works
“It was observed earlier that CAG expansions in an HD mouse model, as well as all germ line and somatic CGG expansions in a Fragile X mouse, were dependent on MutLγ (MLH1-MLH3) [49,50].”
BackgroundMorales, F., Vásquez, M., Corrales, E., Vindas-Smith, R., Santamaría‐Ulloa, C., Zhang, B., Sirito, M., Estecio, M. R., Krahe, R., & Monckton, D. G. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa123 · Cited by 57 · see citing works
MutLγ promotes repeat expansion in a Fragile X mouse model while EXO1 is protective
Zhao, X.-N., Zhang, Y., Wilkins, K. J., Edelmann, W., & Usdin, K. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007719 · Cited by 54 · see citing works
RNA–protein interactions in unstable microsatellite diseases
Mohan, A., Goodwin, M., & Swanson, M. S. (2014) · Brain Research · doi:10.1016/j.brainres.2014.03.039 · Cited by 55 · see citing works
Lai, Y., Budworth, H., Beaver, J. M., Chan, N. L. S., Zhang, Z., McMurray, C. T., & Liu, Y. (2016) · Nature Communications · doi:10.1038/ncomms12465 · Cited by 55 · see citing works
“23), and other MutL homolog (MLH)-related endonucleases 24,25 , also suppresses expansion, bolstering the notion that the MMR pathway contributes to expansion.”
Zhou, Y., Kumari, D., Sciascia, N., & Usdin, K. (2016) · Molecular Autism · doi:10.1186/s13229-016-0105-9 · Cited by 54 · see citing works
Landles, C., Milton, R. E., Ali, N. S., Flomen, R. H., Flower, M. D., Schindler, F., Gomez-Paredes, C., Bondulich, M. K., Osborne, G. F., Goodwin, D., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa066 · Cited by 53 · see citing works
“This somatic instability is recapitulated in mouse models of Huntington’s disease (Mangiarini et al. , 1997) and is prevented in the absence of the mismatch repair genes Msh2 , Msh3 , Mlh1 and Mlh3 (Manley et al. , 1999; Pinto et al. , 2013; Tome et al. , 2013).”
Miller, C. J., Kim, G.-Y., Zhao, X.-N., & Usdin, K. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008902 · Cited by 53 · see citing works
“Expansion in a number of models, including the FXD mouse, has been shown to also require MutLγ, one of the three MutL complexes seen in mammalian cells [13, 24, 25].”
BackgroundBiological Aging and the Cellular Pathogenesis of Huntington’s Disease
Machiela, E., & Southwell, A. L. (2020) · Journal of Huntington s Disease · doi:10.3233/jhd-200395 · Cited by 53 · see citing works
Ament, S. A., Pearl, J. R., Grindeland, A., Claire, J. S., Earls, J. C., Kovalenko, M. V., Gillis, T., Mysore, J. S., Gusella, J. F., Lee, J., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx006 · Cited by 50 · see citing works
Self-citationMcLean, Z. L., Gao, D., Correia, K., Roy, J. C. L., Shibata, S., Farnum, I. N., Valdepenas-Mellor, Z., Kovalenko, M. V., Rapuru, M., Morini, E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47485-0 · Cited by 49 · see citing works
“Instead, modi fi cation by these common haplotypes has been presumed to be due to sequence differences affecting PMS1 , given its relationship with those DNA repair genes where functional variationhasbeenclearlydemonstrated 23,24,41 .”
Self-citationHuntington’s disease: nearly four decades of human molecular genetics
Gusella, J. F., Lee, J., & MacDonald, M. E. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab170 · Cited by 48 · see citing works
“Endogenous models also linked repeat expansion to the timing of emergent phenotype (55,56), including demonstration with a naturally occurring Mlh1 variant that reduced expression levels decreased both the rate of expansion and the rate of striatal neuron pathology (57).”
BackgroundThe dual nature of mismatch repair as antimutator and mutator: for better or for worse
Bak, S. T., Sakellariou, D., & Peña-Dı́az, J. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00287 · Cited by 49 · see citing works
“In this regard, a role for MutLγ in TNR expansion associated with HD has recently been described (Pinto et al., 2013).”
BackgroundHalabi, A., Fuselier, K. T. B., & Grabczyk, E. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky143 · Cited by 48 · see citing works
“Further, MutL has been shown as necessary for all somatic expansions in an HD mouse model (50), substantiating a role for MutL that can be adapted more generally in DNA repeat expansion.”
Chromatin Regulation of DNA Damage Repair and Genome Integrity in the Central Nervous System
Pan, L., Penney, J., & Tsai, L. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.08.001 · Cited by 48 · see citing works
“[134] Pinto RM, Dragileva E, Kirby A, Lloret A, Lopez E, St Claire J, et al.”
Tissue specificity in DNA repair: lessons from trinucleotide repeat instability
Dion, V. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.04.005 · Cited by 46 · see citing works
Lokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005181 · Cited by 45 · see citing works
“Author Summary Unstable microsatellites are responsible for a number of debilitating human diseases known as the Repeat Expansion Diseases.”
BackgroundInfluentialCoordinated and Independent Roles for MLH Subunits in DNA Repair
Pannafino, G., & Alani, E. (2021) · Cells · doi:10.3390/cells10040948 · Cited by 43 · see citing works
“If MLH3 alone is playing a functional role, it must be doing so in a process that is distinct from MMR, trinucleotide repeat expansion, and meiotic crossover resolution, which all require intact MLH1-MLH3 complexes [20,21,34,83,85].”
BackgroundMutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions
Keogh, N., Chan, K. Y., Li, G., & Lahue, R. S. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx650 · Cited by 41 · see citing works
“The misrepair model is also consistent with the requirement for the MutL homologs Pms2, Mlh1 and Mlh3 in driving expansions, as evidenced by the reduced frequency of somatic expansions in knockout mice (27,47).”
Self-citationRoy, J. C. L., Vitalo, A. G., Andrew, M. A., Mota‐Silva, E., Kovalenko, M. V., Burch, Z. N., Nhu, A. M., Cohen, P. E., Grabczyk, E., Wheeler, V. C., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab152 · Cited by 42 · see citing works
Self-citationViterbo, D., Michoud, G., Mosbach, V., Dujon, B., & Richard, G. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.03.002 · Cited by 39 · see citing works
FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats
Porro, A., Mohiuddin, M., Zurfluh, C., Spegg, V., Dai, J., Iehl, F., Ropars, V., Collotta, G., Fishwick, K. M., Mozaffari, N. L., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf7906 · Cited by 41 · see citing works
Self-citationFerguson, R., Goold, R., Coupland, L. A., Flower, M. D., & Tabrizi, S. J. (2024) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.04.015 · Cited by 41 · see citing works
“75 Despite this, the effect we observe upon lowering MLH1 expression is concordant with the reduced repeat expansion reported in multiple Mlh1 null mouse models of HD 23,39 and our previous work in a U2OS cell system.”
Martins, S., Pearson, C. E., Coutinho, P., Provost, S., Amorim, A., Dubé, M., Sequeiros, J., & Rouleau, G. A. (2014) · Human Genetics · doi:10.1007/s00439-014-1467-8 · Cited by 39 · see citing works
“The most studied MSH2, MSH3, PMS2, MLH1, and MLH3 are definitively involved in repeat instability, but the exact mechanism of their action remains unclear as does their relevance to humans (Ezzatizadeh et al. 2012; Pinto et al. 2013).”
BackgroundSelf-citationTALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats
Mosbach, V., Poggi, L., Viterbo, D., Charpentier, M., & Richard, G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.083 · Cited by 38 · see citing works
“2146 Cell Reports 22, 2146–2159, February 20, 2018 a 2018 The Aut This is an open access article under the CC BY license (http://creative player of the expansion process, although its precise role is not totally clear (Foiry et al., 2006; Manley et al., 1999; Owen et al., 2005; Pearson et al., 1997; Pinto et al., 2013…”
BackgroundDrugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases
Benn, C., Gibson, K. R., & Reynolds, D. S. (2020) · Journal of Huntington s Disease · doi:10.3233/jhd-200421 · Cited by 35 · see citing works
Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs
Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J. M., Collins, R. L., Lucente, D. E., Ruliera, J., Gillis, T., et al. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddaa283 · Cited by 38 · see citing works
“Evidence for the rate-to-threshold component points to somatic instability of the expanded repeat, which is an area of active investigation, previously of interest in mouse models (9,10), that is now gaining traction in humans based on the identities of the DNA maintenance modifier genes with variants that produce the…”
BackgroundSelf-citationEpigenetic regulation in Huntington's disease
Hyeon, J. W., Kim, A. H., & Yano, H. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105074 · Cited by 38 · see citing works
Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts
Polyzos, A. A., & McMurray, C. T. (2017) · DNA repair · doi:10.1016/j.dnarep.2017.06.017 · Cited by 35 · see citing works
Smith, E. J., Sathasivam, K., Landles, C., Osborne, G. F., Mason, M. A., Gomez-Paredes, C., Taxy, B. A., Milton, R. E., Ast, A., Schindler, F., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcad010 · Cited by 35 · see citing works
Kovalenko, M. V., Milnerwood, A. J., Giordano, J. V., Claire, J. S., Guide, J. R., Stromberg, M., Gillis, T., Sapp, E., DiFiglia, M., MacDonald, M. E., et al. (2018) · Journal of Huntington s Disease · doi:10.3233/jhd-170282 · Cited by 35 · see citing works
“HttQ111 mice exhibit time-dependent somatic instability, with particularly high levels of expansion in the liver and striatum, correlating with cellular pathogenesis in the latter [21, 24, 39, 40].”
BackgroundSelf-citationMatuszek, Ż., Arbab, M., Kesavan, M., Hsu, A., Roy, J. C. L., Zhao, J., Yu, T., Weisburd, B., Newby, G. A., Doherty, N. J., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02172-8 · Cited by 34 · see citing works
“134,138).”
Self-citationLarson, E., Fyfe, I., Morton, A. J., & Monckton, D. G. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.01.004 · Cited by 34 · see citing works
“Most notably, mouse models have been instrumental in revealing a critical role for the Msh2, Mlh1, Mlh3, Msh3 and Pms2 DNA mismatch repair genes in mediating both somatic and germline expansions (Manley et al., 1999; Kovtun andMcMurray, 2001; van den Broek et al., 2002; Savouret et al., 2003; Gomes-Pereira et al., 200…”
InfluentialGenetic modifiers of repeat expansion disorders
Rajagopal, S., Donaldson, J., Flower, M. D., Moss, D. J. H., & Tabrizi, S. J. (2023) · Emerging Topics in Life Sciences · doi:10.1042/etls20230015 · Cited by 32 · see citing works
Huntington disease: somatic expansion, pathobiology and therapeutics
Donaldson, J., Moss, D. J. H., Ciosi, M., Usdin, K., Balmus, G., Monckton, D. G., & Tabrizi, S. J. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01159-7 · Cited by 33 · see citing works
“Early studies of MMR proteins have shown that MSH2, MSH3, MLH1 and MLH3 are essential for somatic CAG repeat expansions in mice 73–75 , and knockout of Msh2 has also shown phenotypic improvements 76 .”
Neto, J. L., Lee, J., Afridi, A., Gillis, T., Guide, J. R., Dempsey, S., Lager, B., Alonso, I. D. C. M. P., Wheeler, V. C., & Pinto, R. M. (2016) · Genetics · doi:10.1534/genetics.116.195578 · Cited by 33 · see citing works
“…Genetic Research (CHGR)]breedingdatawereobtained for theHttQ111 lineon six background strains: CD1, B6J, C57BL/6NCrl (B6N), 129S2/ SvPasCrlf (129), FVB/NCrl (FVB) and DBA/2J (DBA); as well as forHttQ80 andHttQ92 onCD1 andB6J backgrounds (Wheeler et al. 1999; Lloret et al. 2006; Pinto et al. 2013).”
BackgroundMethodSelf-citationHayward, B. E., Steinbach, P. J., & Usdin, K. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa573 · Cited by 30 · see citing works
Bergonzoni, G., Döring, J., & Biagioli, M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.628010 · Cited by 32 · see citing works
“Knock-out of DNA mismatch repair (MMR) proteins in HdhQ111 knock-in mice showed that Msh2/3/6, Mlh1, and Mlh3 are modifiers of somatic CAG instability (Wheeler, 2003; Dragileva et al., 2009; Pinto et al., 2013).”
BackgroundMSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo
Williams, G. M., & Surtees, J. A. (2015) · Genetics · doi:10.1534/genetics.115.177303 · Cited by 31 · see citing works
Recent advances in genetics of chorea
Mencacci, N. E., & Carecchio, M. (2016) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000352 · Cited by 32 · see citing works
Zhao, X.-N., Kumari, D., Miller, C. J., Kim, G.-Y., Hayward, B. E., Vitalo, A. G., Pinto, R. M., & Usdin, K. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200423 · Cited by 32 · see citing works
“MutL MLH1 ↑ [69] [107] MLH3 ↑ [59] [107] PMS1 ↑ [70] PMS2 ↑ [70] ↓ [65]”
Self-citationBelgrad, J., Tang, Q., Hildebrand, S. R., Summers, A., Sapp, E., Echeverria, D., O’Reilly, D., Luu, E., Bramato, B. M., Allen, S. E., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae368 · Cited by 31 · see citing works
Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation
Ciosi, M., Cumming, S. A., Chatzi, A., Larson, E., Tottey, W., Lomeikaite, V., Hamilton, G. M., Wheeler, V. C., Pinto, R. M., Kwak, S., et al. (2021) · Journal of Huntington s Disease · doi:10.3233/jhd-200433 · Cited by 32 · see citing works
Self-citationLong somatic DNA-repeat expansion drives neurodegeneration in Huntington diseasePreprint
Handsaker, R. E., Kashin, S., Reed, N. M., Tan, S., Lee, W., McDonald, T. M., Morris, K., Kamitaki, N., Mullally, C. D., Morakabati, N. R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.17.592722 · Cited by 31 · see citing works
FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism
Phadte, A. S., Bhatia, M., Ebert, H., Abdullah, H., Elrazaq, E. A., Komolov, K. E., & Pluciennik, A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302103120 · Cited by 30 · see citing works
Activated or Impaired: An Overview of DNA Repair in Neurodegenerative Diseases
Qin, N., Geng, A., & Xue, R. (2022) · Aging and Disease · doi:10.14336/ad.2021.1212 · Cited by 30 · see citing works
“Initially, the mismatch site is recognized by MLH1.”
BackgroundExpanded roles for the MutL family of DNA mismatch repair proteins
Furman, C. M., Elbashir, R., & Alani, E. (2020) · Yeast · doi:10.1002/yea.3512 · Cited by 28 · see citing works
“Lastly, recent studies in yeast and higher eukaryotes have suggested a role for Mlh1–Mlh3 in mediating somatic CAG trinucleotide repeat instability (Pinto et al., 2013; Su & Freudenreich, 2017).”
BackgroundGall-Duncan, T., Luo, J., Jurkovic, C.-M., Fischer, L. A., Fujita, K., Deshmukh, A. L., Harding, R., Tran, S., Mehkary, M. H., Li, V., et al. (2023) · Cell · doi:10.1016/j.cell.2023.09.008 · Cited by 28 · see citing works
Self-citationCis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics
McGinty, R. J., & Mirkin, S. M. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.02.005 · Cited by 27 · see citing works
Akçimen, F., Martins, S., Liao, C., Bourassa, C. V., Catoire, H., Nicholson, G. A., Rieß, O., Raposo, M., França, M. C., Vasconcelos, J., et al. (2020) · Aging · doi:10.18632/aging.102825 · Cited by 27 · see citing works
- Authors
- Pinto, R. M., Dragileva, E., Kirby, A., Lloret, A., Lopez, E., St. Claire, J., Panigrahi, G. B., Hou, C., Holloway, K., Gillis, T., Guide, J. R., Cohen, P. E., Li, G.-M., Pearson, C. E., Daly, M. J., & Wheeler, V. C.
- Affiliations
- Massachusetts General Hospital (US)
- Broad Institute (US)
- University of Toronto (CA)
- University of Kentucky (US)
- Cornell University (US)
- Corresponding author
- Wheeler, Vanessa C.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-31
- Volume
- 9
- Issue
- 10
- Pages
- e1003930
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3814320
- OpenAlex
- W2107416433
- Cited by
- 250
- References
- 100
- Citations by year
- 2026: 20 · 2025: 24 · 2024: 32 · 2023: 26 · 2022: 12 · 2021: 30 · 2020: 27 · 2019: 8 · 2018: 19 · 2017: 16 · 2016: 17 · 2015: 11 · 2014: 7
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM089684, GM089684, R01GM097263)
- National Institute of Neurological Disorders and Stroke (NS049206, R01NS049206)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00HD065870)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- Huntington's disease, CAG repeat instability, somatic repeat expansion, DNA mismatch repair, MLH1, MLH3, MSH2, MSH3, genetic modifiers, strain differences, striatum, DNA repair
- MeSH terms
- MutL Proteins, MutL Protein Homolog 1, Animals, Carrier Proteins, Disease Models, Animal, Humans, Huntington Disease, Nuclear Proteins, RNA, Messenger, Trinucleotide Repeat Expansion, Genomic Instability, Adaptor Proteins, Signal Transducing, Mice, Genome-Wide Association Study, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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