The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
C9orf72 expansion disrupts ATM-mediated chromosomal break repair
Open accessAbstract
Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA–RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.
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DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936 · cited 2×
“Increased R-Loops and defective ATM signalling can account for multiple yet unexplained phenotypes of C9orf72 repeat expansions: (1) increased heterochromatin, (2) increased DSBs, and (3) the previously reported C9orf72-associated splicing defects37.”
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
The ATM protein kinase: regulating the cellular response to genotoxic stress, and more
Shiloh, Y., & Ziv, Y. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3546 · Cited by 1,649
C9orf72 nucleotide repeat structures initiate molecular cascades of disease
Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., et al. (2014) · Nature · doi:10.1038/nature13124 · Cited by 978
Self-citationATM Signaling Facilitates Repair of DNA Double-Strand Breaks Associated with Heterochromatin
Goodarzi, A. A., Noon, A. T., Deckbar, D., Ziv, Y., Shiloh, Y., Löbrich, M., & Jeggo, P. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.05.017 · Cited by 836
ATM-Dependent Chromatin Changes Silence Transcription In cis to DNA Double-Strand Breaks
Shanbhag, N. M., Rafalska-Metcalf, I. U., Balane-Bolivar, C., Janicki, S. M., & Greenberg, R. A. (2010) · Cell · doi:10.1016/j.cell.2010.04.038 · Cited by 737
53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark
Fradet-Turcotte, A., Canny, M. D., Escribano-Díaz, C., Orthwein, A., Leung, C. C. Y., Huang, H., Landry, M.-C., Kitevski-LeBlanc, J., Noordermeer, S. M., Sicheri, F., et al. (2013) · Nature · doi:10.1038/nature12318 · Cited by 686
Noon, A. T., Shibata, A., Rief, N., Löbrich, M., Stewart, G. S., Jeggo, P. A., & Goodarzi, A. A. (2010) · Nature Cell Biology · doi:10.1038/ncb2017 · Cited by 339
The core spliceosome as target and effector of non-canonical ATM signalling
Tresini, M., Warmerdam, D. O., Kolovos, P., Snijder, L., Vrouwe, M. G., Demmers, J. A. A., van IJcken, W. F. J., Grosveld, F. G., Medema, R. H., Hoeijmakers, J. H. J., et al. (2015) · Nature · doi:10.1038/nature14512 · Cited by 252
Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models
Difilippantonio, S., Celeste, A., Fernandez-Capetillo, O., Chen, H.-T., Martin, B. R. S., Laethem, F. V., Yang, Y.-P., Petukhova, G. V., Eckhaus, M., Feigenbaum, L., et al. (2005) · Nature Cell Biology · doi:10.1038/ncb1270 · Cited by 227
Cited by
C9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
Mead, R. J., Shan, N., Reiser, H. J., Marshall, F., & Shaw, P. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00612-2 · Cited by 505
Self-citationWang, H., Guo, W., Mitra, J., Hegde, P. M., Vandoorne, T., Eckelmann, B. J., Mitra, S., Tomkinson, A. E., Van Den Bosch, L., & Hegde, M. L. (2018) · Nature Communications · doi:10.1038/s41467-018-06111-6 · Cited by 205
Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease
Shanbhag, N. M., Evans, M. D., Mao, W., Nana, A. L., Seeley, W. W., Adame, A., Rissman, R. A., Masliah, E., & Mucke, L. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0723-5 · Cited by 214
Boivin, M., Pfister, V., Gaucherot, A., Ruffenach, F., Negroni, L., Sellier, C., & Charlet‐Berguerand, N. (2020) · The EMBO Journal · doi:10.15252/embj.2018100574 · Cited by 137
Metadata
- Authors
- Walker, C., Herranz-Martin, S., Karyka, E., Liao, C., Lewis, K., Elsayed, W., Lukashchuk, V., Chiang, S.-C., Ray, S., Mulcahy, P. J., Jurga, M., Tsagakis, I., Iannitti, T., Chandran, J., Coldicott, I., De Vos, K. J., Hassan, M. K., Higginbottom, A., Shaw, P. J., Hautbergue, G. M., Azzouz, M., & El-Khamisy, S. F.
- Venue
- Nature Neuroscience
- Published
- 2017-07-17
- Volume
- 20
- Issue
- 9
- Pages
- 1225-1235
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2734373506
- Cited by
- 185
- References
- 13
- FWCI
- 12.20
- Type
- journal article
- Language
- en
- Open access
- green
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- Walker, C., Herranz-Martin, S., Karyka, E., Liao, C., Lewis, K., Elsayed, W., Lukashchuk, V., Chiang, S.-C., Ray, S., Mulcahy, P. J., Jurga, M., Tsagakis, I., Iannitti, T., Chandran, J., Coldicott, I., De Vos, K. J., Hassan, M. K., Higginbottom, A., Shaw, P. J., . . . El-Khamisy, S. F. (2017). C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nature Neuroscience. https://doi.org/10.1038/nn.4604
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