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Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway
Open accessAbstract
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.
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“ALT is associated with mutations in the chromatin remodeller α-thalassaemia/mental retardation syndrome X-linked (AT R X ) both in vitro and in several human cancers, including glioblastomas162–165.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [162]
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Cites
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“0 algorithm was performed as previously described on the resulting segmented copy number data from the 22 ALT lines [39,59].”
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“0 algorithm was performed as previously described on the resulting segmented copy number data from the 22 ALT lines [39,59].”
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“The same correlation between inactivation of the ATRX pathway and the ALT-like phenotype was observed in pediatric glioblastoma and several other cancers [16,26].”
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“In cells that have been immortalized by telomerase activation, the telomere-driven genome instability is largely dampened, resulting in a rearranged but now relatively stable karyotype [43,44].”
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“Recently, a subset of pancreatic neuroendocrine tumors (PanNETs) were found to have ultrabright telomeric FISH signals, suggesting the presence of ALT-like long telomeres [24,25].”
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“In addition to shelterin and TERRA, we analyzed 299 genes with potential relevance to telomeres and the ALT pathway.”
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Items 101–200 of 627
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“In addition, these data are explicative of the genetic instability, and altered DNA damage response in ALT cell lines [15,81,82], besides providing a molecular target that can be explored to design new targeted therapies regarding ALT-positive gliomas.”
BackgroundInfluentialNuclear-Receptor-Mediated Telomere Insertion Leads to Genome Instability in ALT Cancers
Marzec, P., Armenise, C., Pérot, G., Roumelioti, F., Basyuk, E. I., Gagos, S., Chibon, F., & Déjardin, J. (2015) · Cell · doi:10.1016/j.cell.2015.01.044 · Cited by 103
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“ALT is associated with extensive genome rearrangements and defects in double-strand break repair (Lovejoy et al. 2012), reviewed in (O’Sullivan and Almouzni 2014).”
BackgroundThe Histone Variant H3.3 in Transcriptional Regulation and Human Disease
Shi, L., Wen, H., & Shi, X. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.11.019 · Cited by 105
“3 mutations, including inactivating mutations of the ATRX and DAXX genes [99–101], which is frequently associated with abnormal telomeres in tumors [104, 105], and activating mutations of the activin receptor type 1 (ACVR1) gene, which functions in the BMP signaling pathway [106–109].”
BackgroundSolving the Telomere Replication Problem
Maestroni, L., Matmati, S., & Coulon, S. (2017) · Genes · doi:10.3390/genes8020055 · Cited by 94
“Moreover, ATRX mutations are frequently found in ALT cancer cells [98].”
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Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers
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Levy, M. A., Kernohan, K. D., Jiang, Y. Y., & Bérubé, N. G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu596 · Cited by 97
Tummala, H., Kirwan, M., Walne, A. J., Hossain, U., Jackson, N. M., Pondarré, C., Plagnol, V., Vulliamy, T., & Dokal, I. S. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.01.007 · Cited by 92
Telomere dynamic in humans and animals: Review and perspectives in environmental toxicology
Louzon, M., Cœurdassier, M., Gimbert, F., Pauget, B., & de Vaufleury, A. (2019) · Environment International · doi:10.1016/j.envint.2019.105025 · Cited by 91
Chromatin Structure in Telomere Dynamics
Galati, A., Micheli, E., & Cacchione, S. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00046 · Cited by 98
“, 2012) and with the establishment of a ALT mechanism of telomere maintenance (Lovejoy et al., 2012).”
BackgroundNguyen, D. N., Heaphy, C. M., de Wilde, R. F., Orr, B. A., Odia, Y., Eberhart, C. G., Meeker, A. K., & Rodríguez, F. J. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00630.x · Cited by 92
“ATRX loss is also present in the majority of cell lines demonstrating ALT (14).”
BackgroundSelf-citationDanussi, C., Bose, P., Parthasarathy, P. T., Silberman, P. C., Arnam, J. S. V., Vitucci, M., Tang, O. Y., Heguy, A., Wang, Y., Chan, T. A.-T., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03476-6 · Cited by 91
Alternative lengthening of telomeres: remodeling the telomere architecture
Conomos, D., Pickett, H. A., & Reddel, R. R. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00027 · Cited by 92
“Recent studies of ALT tumors and immortalized cell lines found a strong correlation between telomere maintenance by ALT and loss of activity of the switch/sucrose non-fermentable (SWI/SNF) family ATP-dependent helicase (ATRX) or its binding partner death-associated protein 6 (DAXX; Heaphy et al., 2011; Bower et al., 2…”
BackgroundInfluentialSelf-citationLiau, J., Lee, J., Tsai, J., Yang, C., Liu, T., Ke, Z.-L., Hsu, H.-H., & Jeng, Y. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.114 · Cited by 85
Hu, Y., Shi, G. W., Zhang, L., Li, F., Jiang, Y., Jiang, S., Ma, W., Zhao, Y. B., Songyang, Z., & Huang, J. (2016) · Scientific Reports · doi:10.1038/srep32280 · Cited by 87
“They are chromatin remodeling factors at telomeres, which are responsible for ALT activity 32,33 .”
InfluentialAlternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends
Hoang, S. M., & O’Sullivan, R. J. (2020) · Trends in cancer · doi:10.1016/j.trecan.2019.12.009 · Cited by 85
ALT Positivity in Human Cancers: Prevalence and Clinical Insights
MacKenzie, D., Watters, A. K., To, J. T., Young, M. W., Muratori, J., Wilkoff, M. H., Abraham, R. G., Plummer, M. M., & Zhang, D. (2021) · Cancers · doi:10.3390/cancers13102384 · Cited by 93
“They also assessed a panel of seven OS cell lines with TRF assay, including U2OS and Saos-2, which are two of the most commonly used cell lines for investigating the ALT pathway.”
ResultInfluentialChaurasia, A., Park, S., Seo, J., & Park, C. (2016) · Journal of Korean Medical Science · doi:10.3346/jkms.2016.31.8.1208 · Cited by 87
Valle‐García, D., Qadeer, Z. A., McHugh, D., Ghiraldini, F. G., Chowdhury, A. H., Hasson, D., Dyer, M. A., Targa, F. R., & Bernstein, E. (2016) · Epigenetics · doi:10.1080/15592294.2016.1169351 · Cited by 88
Ohba, S., Mukherjee, J., See, W. L., & Pieper, R. O. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0924 · Cited by 81
“It is worth considering, however, that mutant IDH1 tumor cells are typically also defective in telomere maintenance, and rely on an alternative (ALT) mechanism rather than telomerase upregulation to elongate their telomeres (13, 44).”
BackgroundBower, K., Napier, C. E., Cole, S. L., Dagg, R. A., Lau, L. M. S., Duncan, E. L., Moy, E. L., & Reddel, R. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050062 · Cited by 84
“Loss of ATRX/DAXX function has therefore been proposed to be involved in activating ALT [16,18].”
BackgroundResultInfluentialSelf-citationCTCF driven TERRA transcription facilitates completion of telomere DNA replication
Beishline, K., Vladimirova, O. V., Tutton, S., Wang, Z., Deng, Z., & Lieberman, P. M. (2017) · Nature Communications · doi:10.1038/s41467-017-02212-w · Cited by 79
The genomic landscape of phaeochromocytoma
Flynn, A., Benn, D. E., Clifton-Bligh, R. J., Robinson, B. G., Trainer, A. H., James, P. A., Hogg, A., Waldeck, K., George, J., Li, J., et al. (2014) · The Journal of Pathology · doi:10.1002/path.4503 · Cited by 81
“ATRX has also been implicated in the Alternate Lengthening of Telomeres (ALT) mechanism identified in a range of cancer types (Lovejoy et al., 2012).”
BackgroundYoshida, M., Ogawa, R., Yoshida, H., Maeshima, A. M., Kanai, Y., Kinoshita, T., Hiraoka, N., & Sekine, S. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.326 · Cited by 81
“In contrast, none of the tumors showed loss of ATRX or DAXX, which are involved in ALT (Heaphy et al, 2011; Lovejoy et al, 2012).”
Pathways for maintenance of telomeres and common fragile sites during DNA replication stress
Özer, Ö., & Hickson, I. D. (2018) · Open Biology · doi:10.1098/rsob.180018 · Cited by 83
Expression and differential regulation of human TERRA at several chromosome ends
Feretzaki, M., Nunes, P. R., & Lingner, J. (2019) · RNA · doi:10.1261/rna.072322.119 · Cited by 81
“A couple of transcription factors have been identified to regulate TERRA expression including CTCF, ATRX, NRF1, HSF1, Snail, and p53 (Deng et al. 2012; Lovejoy et al. 2012; Episkopou et al. 2014; Eid et al. 2015; Flynn et al. 2015; Diman et al. 2016; Tutton et al. 2016; Koskas et al. 2017; Mazzolini et al. 2018).”
BackgroundInfluentialHigh resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer
Schmidt, T. T., Tyer, C., Rughani, P., Haggblom, C., Jones, J. R., Dai, X., Frazer, K. A., Gage, F. H., Juul, S., Hickey, S. F., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48917-7 · Cited by 85
“…that telomeric reads of TERT + cancer cell lines overall map better to the pangenome reference than the frequently genetically more unstable ALT + cancer samples 52 emphasizes the connection between mapping quality and the sample ’ s similarity to the reference genome (Supplementary Tables 5, 6).”
Telomere Maintenance Mechanisms in Cancer: Clinical Implications
Reddel, R. R. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140630101047 · Cited by 82
“Activation of ALT in tumors is commonly associated with loss of expression of the ATRX or DAXX genes, which encode proteins with multiple proposed functions that include chromatin remodeling, especially at the telomere, and resistance to various cellular stresses [120, 127-133].”
BackgroundSelf-citationCentromeric and ectopic assembly of CENP-A chromatin in health and cancer: old marks and new tracks
Sharma, A. B., Dimitrov, S. I., Hamiche, A., & Dyck, E. V. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1298 · Cited by 82
“protein expression and an abnormal mechanism of telomere maintenance called Alternative Lengthening of Telomeres (ALT) (208,213,214), which is linked to chromosomal instability (215).”
BackgroundEmerging Roles of ATRX in Cancer
Watson, L. A., Goldberg, H. E., & Bérubé, N. G. (2015) · Epigenomics · doi:10.2217/epi.15.82 · Cited by 82
Reconstructing the molecular life history of gliomas
Barthel, F. P., Wesseling, P., & Verhaak, R. G. W. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1842-y · Cited by 86
“The presence or absence of inactivating ATRX and DAXX mutations present a strong correlation with ALT in many tumor types including gliomas [84, 133, 191].”
BackgroundThe Response to DNA Damage at Telomeric Repeats and Its Consequences for Telomere Function
Doksani, Y. (2019) · Genes · doi:10.3390/genes10040318 · Cited by 83
Distinct roles of RAD52 and POLQ in chromosomal break repair and replication stress response
Kelso, A. A., Lopezcolorado, F. W., Bhargava, R., & Stark, J. M. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008319 · Cited by 75
ATRX Loss in Glioma Results in Epigenetic Dysregulation of Cell Cycle Phase Transition
Qin, T., Mullan, B. P., Ravindran, R., Messinger, D., Siada, R. G., Cummings, J. R., Harris, M. K., Muruganand, A., Pyaram, K., Miklja, Z., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110216 · Cited by 85
Self-citationChang, F. T. M., McGhie, J. D. R., Chan, F. L., Tang, M. C. W., Anderson, M. A., Mann, J. R., Choo, K. H. A., & Wong, L. H. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt114 · Cited by 83
DNA Replication Origins and Fork Progression at Mammalian Telomeres
Higa, M., Fujita, M., & Yoshida, K. (2017) · Genes · doi:10.3390/genes8040112 · Cited by 81
Han, B. R., Cai, J., Gao, W., Meng, X., Gao, F., Wu, P., Duan, C., Wang, R., Dinislam, M., Lin, L., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.056 · Cited by 74
Le, R.-R., Huang, Y., Zhang, Y.-P., Wang, H., Lin, J.-M., Dong, Y., Li, Z., Guo, M., Kou, X.-C., Zhao, Y.-H., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.11.018 · Cited by 51
Telomere regulation in pluripotent stem cells
Huang, Y. Y., Liang, P., Liu, D., Huang, J., & Songyang, Z. (2014) · Protein & Cell · doi:10.1007/s13238-014-0028-1 · Cited by 70
“Additionally, genome instability and altered double-strand break (DSB) repair are also correlated with ALT (Lovejoy et al., 2012).”
BackgroundTelomere elongation chooses TERRA ALTernatives
Arora, R., & Azzalin, C. M. (2015) · RNA Biology · doi:10.1080/15476286.2015.1065374 · Cited by 73
“Already in the very first reports on TERRA discovery it was shown that osteosarcomaderived U2OS cells, ALT cells commonly used in laboratories, contained elevated levels of TERRA as compared to telomerasepositive cancer cells or primary human fibroblasts.22,23 Successive work employing additional ALT cells has indeed…”
BackgroundInfluentialBrosnan‐Cashman, J. A., Yuan, M., Graham, M. K., Rizzo, A. J., Myers, K. M., Davis, C., Zhang, R., Esopi, D., Raabe, E. H., Eberhart, C. G., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0204159 · Cited by 67
Self-citationATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress
Cabral, J. M., Oh, H. S., & Knipe, D. M. (2018) · eLife · doi:10.7554/elife.40228 · Cited by 69
“gene are linked to a developmental disorder and several cancer types (18).”
BackgroundInfluentialLu, R., & Pickett, H. A. (2022) · Open Biology · doi:10.1098/rsob.220011 · Cited by 75
Chang, F. T. M., Chan, F. L., McGhie, J. D. R., Udugama, M., Mayne, L. V., Collas, P., Mann, J. R., & Wong, L. H. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv104 · Cited by 73
“Telomerase-null ALT cancer cells generally contain extensive genomic instability, as indicated by severe chromosomal fragmentation, frequent micronucleation, a high basal level of DNA damage foci and elevated DNA damage response (DDR) signaling in the absence of exogenous damage (6,7).”
BackgroundResultInfluentialLinking Telomere Regulation to Stem Cell Pluripotency
Liu, L. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.10.007 · Cited by 66
Zhang, T., Zhang, Z., Shengzhao, G., Li, X., Liu, H., & Zhao, Y. B. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007925 · Cited by 68
Telomeres and Cancer: Resolving the Paradox
Nassour, J., Schmidt, T. T., & Karlseder, J. (2021) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050420-023410 · Cited by 70
“This is supported by another study indicating that telomeric damage and increased recombination, which are both hallmarks of ALT, are induced in the absence of ATRX due to the transient loss of macroH2A1.”
BackgroundInfluentialGEP- NETS UPDATE: Genetics of neuroendocrine tumors
Crona, J., & Skogseid, B. M. (2016) · European Journal of Endocrinology · doi:10.1530/eje-15-0972 · Cited by 71
Break-induced replication promotes fragile telomere formationPreprint
Yang, Z., Takai, K., Lovejoy, C. A., & de Lange, T. (2020) · Genes & Development · doi:10.1101/gad.328575.119 · Cited by 66
“ALT and non-ALT human cell lines were described previously (Cristofari and Lingner 2006; Takai et al. 2010; Lovejoy et al. 2012) and cultured with 10% fetal bovine serum (Gibco) with the same supplements.”
MethodSelf-citationAssembly of telomeric chromatin to create ALTernative endings
O’Sullivan, R. J., & Almouzni, G. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.07.007 · Cited by 66
ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
Lovejoy, C. A., Takai, K., Huh, M. S., Picketts, D. J., & de Lange, T. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000594 · Cited by 64
“ALT cell lines used in this study have been described previously [17].”
BackgroundMethodInfluentialSelf-citationKamranvar, S. A., Chen, X., & Masucci, M. G. (2013) · Oncogene · doi:10.1038/onc.2013.189 · Cited by 61
TelNet - a database for human and yeast genes involved in telomere maintenance
Braun, D. M., Chung, I., Kepper, N., Deeg, K. I., & Rippe, K. (2018) · BMC Genetics · doi:10.1186/s12863-018-0617-8 · Cited by 60
“Gene set with potential relevance to telomeres and the ALT pathway human / various 297 [41]”
BackgroundMolecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas
Wong, Q. H., Li, K. K., Wang, W., Malta, T. M., Noushmehr, H., Grabovska, Y., Jones, C., Chan, A. K., Kwan, J. S. H., Huang, Q. J., et al. (2021) · Modern Pathology · doi:10.1038/s41379-021-00778-x · Cited by 60
Self-citationG-quadruplexes mark alternative lengthening of telomeres
Yang, S. Y. C., Chang, E. Y., Lim, J., Kwan, H., Monchaud, D., Yip, S. S. F., Stirling, P. C., & Wong, J. M. Y. (2021) · NAR Cancer · doi:10.1093/narcan/zcab031 · Cited by 61
“%) do not harbour defective ATRX / DAXX (12,53).”
InfluentialHistone Variants: The Nexus of Developmental Decisions and Epigenetic Memory
Loppin, B., & Berger, F. (2020) · Annual Review of Genetics · doi:10.1146/annurev-genet-022620-100039 · Cited by 57
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Lee, J., Jeng, Y., Liau, J., Tsai, J., Hsu, H.-H., & Yang, C. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.67 · Cited by 58
Nasirden, A., Saito, T., Fukumura, Y., Hara, K., Akaike, K., Kurisaki‐Arakawa, A., Asahina, M., Yamashita, A., Tomomasa, R., Hayashi, T., et al. (2016) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-016-2027-5 · Cited by 59
Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands
Min, J., Wright, W. E., & Shay, J. W. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkw1295 · Cited by 61
“The excessive amounts of C-circles that exist in ALT cells may be important in ALT activity (15,21,32,41,42).”
InfluentialPheochromocytoma: A Genetic And Diagnostic Update
MERCADO-ASIS, L. B., Wolf, K. I., Jochmanová, I., & Taïeb, D. (2017) · Endocrine Practice · doi:10.4158/ep-2017-0057 · Cited by 58
“For instance, ATRX gene is involved in telomere maintenance and chromosome integrity (24), as well as in the gene expression and transcriptional repression of non-coding Telomeric Repeat-containing RNA (TERRA) (25).”
BackgroundRegulation of ALT-associated homology-directed repair by polyADP-ribosylation
Hoang, S. M., Kaminski, N., Bhargava, R., González, J. B., Lynskey, M. L., García-Expósito, L., Roncaioli, J. L., Wondisford, A. R., Wallace, C. T., Watkins, S. C., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0512-7 · Cited by 61
Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma
Agnihotri, S., Aldape, K., & Zadeh, G. M. (2014) · Neurosurgical FOCUS · doi:10.3171/2014.9.focus14505 · Cited by 59
DNA:RNA hybrids at telomeres – when it is better to be out of the (R) loop
Toubiana, S., & Selig, S. (2018) · FEBS Journal · doi:10.1111/febs.14464 · Cited by 56
DAXX-ATRX regulation of p53 chromatin binding and DNA damage response
Gulve, N., Su, C., Deng, Z., Soldan, S. S., Vladimirova, O. V., Wickramasinghe, J. M., Zheng, H., Kossenkov, A. V., & Lieberman, P. M. (2022) · Nature Communications · doi:10.1038/s41467-022-32680-8 · Cited by 53
ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors
Chou, A. S. Y., Itchins, M., de Reuver, P. R., Arena, J., Clarkson, A., Sheen, A., Sioson, L., Cheung, V. K.-Y., Perren, A. A., Nahm, C. B., et al. (2018) · Human Pathology · doi:10.1016/j.humpath.2018.07.032 · Cited by 55
“Loss of function of either of these proteins leads to telomere dysfunction and results in impaired non-homologous end joining, alternate lengthening of telomeres (ALT) and general genomic instability [12-14].”
BackgroundMolecular Markers in Low-Grade Glioma—Toward Tumor Reclassification
Olar, A., & Sulman, E. P. (2015) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2015.02.006 · Cited by 56
Favero, F., McGranahan, N., Salm, M. P., Birkbak, N. J., Sanborn, Z., Benz, S. C., Becq, J., Peden, J. F., Kingsbury, Z., Grocock, R., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv127 · Cited by 56
“These genes have previously been described as driver events for GBM [4, 13], and ATRX mutations has been shown to co-occur with TP53 and IDH1 mutations [2], and to be a driver of alternative telomere lengthening [14].”
BackgroundTelomere chromatin establishment and its maintenance during mammalian development
Tardat, M., & Déjardin, J. (2017) · Chromosoma · doi:10.1007/s00412-017-0656-3 · Cited by 59
“Interestingly, absence of ATRX expression or localization at telomeres is a frequent feature of ALT cancer cell lines (Heaphy et al. 2011; Lovejoy et al. 2012) (Fig.”
BackgroundMechanisms that drive telomere maintenance and recombination in human cancers
Sobinoff, A. P., & Pickett, H. A. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.02.006 · Cited by 57
The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair
Böhm, S., & Bernstein, K. A. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.07.007 · Cited by 54
“While most cancers reactivate telomerase, a significant proportion initiate the ALT-pathway [100], and links of ALT activation to tumors with complex karyotypes have been reported [101-103].”
BackgroundNersisyan, L., Hopp, L., Loeffler‐Wirth, H., Galle, J., Loeffler, M., Arakelyan, A., & Binder, H. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01172 · Cited by 55
“Altogether, our data indicate that TEL is the major TMM in the CRC cases studied, while the ALT pathway additionally activates mainly in MSI s-CRC due to the concerted action of a number of factors, among them the HR and APB TMM branches as the main drivers.”
BackgroundInfluentialLiau, J., Tsai, J., Yang, C., Lee, J., Liang, C., Hsu, H.-H., & Jeng, Y. (2015) · Human Pathology · doi:10.1016/j.humpath.2015.05.019 · Cited by 54
“Although loss of DAXX is more common than loss of ATRX in pancreatic neuroendocrine tumors [11], loss of ATRX is much more frequent in ALT-positive gliomas, leiomyosarcomas, and cell lines [11,14,21].”
BackgroundClinical features of ATRX or DAXX mutated neuroblastoma
Kurihara, S., Hiyama, E., Onitake, Y., Yamaoka, E., & Hiyama, K. (2014) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2014.09.029 · Cited by 55
Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers
Ichimura, K., Narita, Y., & Hawkins, C. E. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1439-7 · Cited by 56
“presence of alternative lengthening of telomeres (ALT) in diverse cancers such as pancreatic neuroendocrine tumours, neuroblastomas, paediatric high grade gliomas, as well as immortalized human fibroblasts [27, 46, 81, 84, 125].”
PML Nuclear Body Biogenesis, Carcinogenesis, and Targeted Therapy
Li, Y., Ma, X., Wu, W., Zhu, C., & Meng, G. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.05.005 · Cited by 56
Mangerel, J., Price, A. J., Castelo‐Branco, P., Brzezinski, J. J., Buczkowicz, P., Rakopoulos, P., Merino, D. M., Baskin, B., Wasserman, J. D., Mistry, M., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1348-1 · Cited by 52
“3 (the product of the H3f3a gene) at the telomeres, favoring formation of heterochromatin [30, 44].”
BackgroundOppel, F., Tao, T., Shi, H., Ross, K. N., Zimmerman, M. W., He, S., Tong, G., Aster, J. C., & Look, A. T. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008039 · Cited by 53
The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours
Pipinikas, C., Berner, A., Sposito, T., & Thirlwell, C. (2019) · Endocrine Related Cancer · doi:10.1530/erc-19-0175 · Cited by 52
BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response
Jiang, H., Zhang, T., Kaur, H., Shi, T., Krishnan, A., Kwon, Y., Sung, P., & Greenberg, R. A. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.03.011 · Cited by 53
Self-citationMutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas
Udugama, M., Hii, L. L., Garvie, A., Cervini, M., Vinod, B., Chan, F. L., Das, P. P., Mann, J. R., Collas, P., Voon, H. P. J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22543-z · Cited by 54
Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease
Sanchez, S. E., Gu, Y., Wang, Y., Golla, A., Martin, A., Shomali, W. E., Hockemeyer, D. F., Savage, S. A., & Artandi, S. E. (2024) · Nature Communications · doi:10.1038/s41467-024-49007-4 · Cited by 57
“In a minority of cancers, an alternative, homologous recombination-dependent telomere lengthening mechanism (ALT) is responsible for maintaining telomere length 12,13 .”
Eid, R., Demattei, M.-V., Episkopou, H., Augé‐Gouillou, C., Decottignies, A., Grandin, N., & Charbonneau, M. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.01317-14 · Cited by 49
BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage
Jensen, R. B., Özeş, A., Kim, T., Estep, A., & Kowalczykowski, S. C. (2013) · DNA repair · doi:10.1016/j.dnarep.2012.12.007 · Cited by 52
The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening
Kim, J., Sun, C., Tran, A. D., Chin, P.-J., Ruiz, P. D., Wang, K., Gibbons, R. J., Gamble, M. J., Liu, Y., & Oberdoerffer, P. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0192-3 · Cited by 52
Gastroenteropancreatic endocrine tumors
Weil, C. (1985) · Journal of Molecular Medicine · doi:10.1007/bf01731493 · Cited by 47
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 50
“Other uncategorized ATPase remodelers include ERCC6/CSB (Cockayne syndrome group B), ATRX (alpha thalassemia/mental retardation syndrome X-linked) and Rad54L [61–65].”
Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials
Yao, J. C., Garg, A. D., Chen, D., Capdevila, J., Engstrom, P. F., Pommier, R. F., Cutsem, E. V., Singh, S., Fazio, N., He, W., et al. (2019) · Endocrine Related Cancer · doi:10.1530/erc-18-0332 · Cited by 50
Emerging roles of telomeric chromatin alterations in cancer
Cacchione, S., Biroccio, A., & Rizzo, A. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1030-5 · Cited by 47
Telomere sequence content can be used to determine ALT activity in tumours
Lee, M., Teber, E., Holmes, O., Nones, K., Patch, A., Dagg, R. A., Lau, L. M. S., Lee, J. H. Y., Napier, C. E., Arthur, J. W., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky297 · Cited by 48
Self-citationMolecularly Targeted Therapy for Neuroblastoma
Greengard, E. G. (2018) · Children · doi:10.3390/children5100142 · Cited by 47
Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma
Fan, H., Chen, C., Chi, C.-S., Tsai, J., Chiang, K.-L., Chang, Y., Lin, S., & Harn, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010200 · Cited by 48
Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis
Light, N. D., Layeghifard, M., Attery, A., Subasri, V., Zatzman, M., Anderson, N. D., Hatkar, R., Blay, S., Chen, D. D., Novokmet, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35727-y · Cited by 47
ATRX and the replication of structured DNA
Clynes, D., & Gibbons, R. J. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.01.005 · Cited by 48
Metadata
- Authors
- Lovejoy, C. A., Li, W., Reisenweber, S., Thongthip, S., Bruno, J., de Lange, T., De, S., Petrini, J. H. J., Sung, P. A., Jasin, M., Rosenbluh, J., Zwang, Y., Weir, B. A., Hatton, C., Ivanova, E., Macconaill, L., Hanna, M., Hahn, W. C., Lue, N. F., Reddel, R. R., Jiao, Y., Kinzler, K., Vogelstein, B., Papadopoulos, N., Meeker, A. K., & for the ALT Starr Cancer Consortium
- Affiliations
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Cornell University (US)
- The University of Sydney (AU)
- Johns Hopkins University (US)
- ORCID
- Lovejoy, Courtney A.
- Thongthip, Supawat
- Bruno, Joanne
- De, Saurav
- Petrini, John H. J.
- Sung, Patricia A.
- Jasin, Maria
- Rosenbluh, Joseph
- Zwang, Yaara
- Hatton, Charlie
- Ivanova, Elena
- Macconaill, Laura
- Hahn, William C.
- Lue, Neal F.
- Reddel, Roger R.
- Jiao, Yuchen
- Kinzler, Kenneth
- Vogelstein, Bert
- Papadopoulos, Nickolas
- Meeker, Alan K.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-19
- Volume
- 8
- Issue
- 7
- Pages
- e1002772
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3400581
- OpenAlex
- W1999626396
- Cited by
- 629
- References
- 60
- Citations by year
- 2026: 34 · 2025: 41 · 2024: 33 · 2023: 44 · 2022: 51 · 2021: 52 · 2020: 49 · 2019: 54 · 2018: 53 · 2017: 44 · 2016: 41 · 2015: 49 · 2014: 44 · 2013: 33 · 2012: 6
- FWCI
- 28.08
- 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)
- 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
- U.S. Department of Defense
- National Institutes of Health
- Cancer Council NSW
- National Institute on Aging (R01AG023145)
- National Cancer Institute (CA076027, R01CA076027, R37CA043460, R13CA162528)
- National Institute of General Medical Sciences (R37GM059413, R37GM049046, R01GM049046, F32GM090437, GM049046, R01GM056888)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- alternative lengthening of telomeres, ATRX, histone H3.3, genomic instability, DNA damage response, DNA double-strand break repair, G2/M checkpoint, micronucleation, genome rearrangement, telomere maintenance
- MeSH terms
- X-linked Nuclear Protein, DNA Damage, DNA Repair, DNA Helicases, HeLa Cells, Histones, Humans, Nuclear Proteins, Signal Transduction, Telomere, Molecular Chaperones, Telomerase, Chromatin Assembly and Disassembly, Genomic Instability, Adaptor Proteins, Signal Transducing, DNA Breaks, Double-Stranded, Co-Repressor Proteins, Telomere Homeostasis, G2 Phase Cell Cycle Checkpoints, Homologous Recombination
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