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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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“The implication of ATRX and DAXX in the ALT phenotype may have some relevance to the checkpoint defects observed, as the involvement of chromatin remodelers in the DDR becomes increasingly clear [55].”
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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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Sun, H., Chen, G., Guo, B., Lv, S., & Yuan, G. (2023) · Journal of Cancer · doi:10.7150/jca.80097 · Cited by 11
“ALT in cancer is associated with the loss of the chromatin remodeling protein ATRX [101, 175].”
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Hsieh, Y.-H., Tai, C.-H., Yeh, M.-T., Chen, Y., Yang, P.-C., Yen, C.-P., Shen, H.-J., Yeh, C.-H., Kuo, H., Han, D., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf597 · Cited by 13
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Gao, L., Natov, N. S., Daly, K. P., Masud, F., Chaudhry, S., Sterling, M. J., & Saif, M. W. (2018) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000000633 · Cited by 11
Nordfors, K., Haapasalo, J. A., Afyounian, E., Tuominen, J. I., Annala, M., Häyrynen, S., Karhu, R., Helén, P., Lohi, O., Nykter, M., et al. (2018) · Molecular Case Studies · doi:10.1101/mcs.a002246 · Cited by 11
“Approximately 10%–15% of human cancers are suspected to use the ALT pathway, including a subset of nervous system tumors (e.g., medulloblastoma, low-grade diffuse gliomas, and ganglioneuroblastoma) (Lovejoy et al. 2012).”
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Nassour, J., & Karlseder, J. (2025) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041688 · Cited by 16
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“…ATRX or DAXX point mutations, a significant overrepresentation over the complete Depmap Avana CRISPR cell line compendium [4.5 %, 36/808 (21Q1)] (hyperge-ometric test P = 0.038) suggesting that ALT characteristics correlate with vulnerability to loss of SUB1/PC4 [Dataset S6 and ( 10 , 42 )].”
InfluentialMultiple functions of the ALT favorite helicase, BLM
Chang, S., Jiang, T., Bao, R., Zhang, Y., Tong, J., Jia, T., Liu, J., Dan, J., & Jia, S. (2025) · Cell & Bioscience · doi:10.1186/s13578-025-01372-3 · Cited by 10
“Supporting this, the ATRX/DAXX complex is commonly mutated in ALT cell lines, leading to nucleosome assembly defects that likely contribute to chromatin remodeling and increased replication stress [13, 14].”
The epigenetic–metabolic interplay in gliomagenesis
Phasaludeen, B., Emerald, B. S., & Ansari, S. A. (2022) · Open Biology · doi:10.1098/rsob.210350 · Cited by 10
Diagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging
Kopp, R. M., Espinosa-Olarte, P., & Alonso‐Gordoa, T. (2022) · Cancers · doi:10.3390/cancers14102514 · Cited by 9
“The inactivation of DAXX/ATRX complex has been related to chromosomal instability and correlated with alternative lengthening of telomeres (ALT), as a senescence scape mechanism induced by telomere shortening in many tumours [40].”
BackgroundATRX modulates the escape from a telomere crisis
Geiller, H. E. B., Harvey, A., Jones, R. E., Grimstead, J. W., Cleal, K., Hendrickson, E. A., & Baird, D. M. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010485 · Cited by 11
ALTercations at telomeres: stress, recombination and extrachromosomal affairs
Loe, T. K., Denchi, E. L., Tricola, G. M., & Azeroglu, B. (2023) · Biochemical Society Transactions · doi:10.1042/bst20230265 · Cited by 10
Telomeres cooperate with the nuclear envelope to maintain genome stability
Rai, R., Sodeinde, T., Boston, A. M., & Chang, S. S. (2023) · BioEssays · doi:10.1002/bies.202300184 · Cited by 9
“[89,90] ATRX forms a complex with H3.”
BackgroundHow to Tackle Challenging ChIP-Seq, with Long-Range Cross-Linking, Using ATRX as an Example
Truch, J., Telenius, J. M., Higgs, D. R., & Gibbons, R. J. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8663-7_6 · Cited by 10
“Since then, ATRX mutations have also been associated with a subset of cancers using the telomerase-independent Alternative Lengthening of Telomeres pathway to maintain their telomere length [26,27].”
BackgroundGastroenteropancreatic neuroendocrine tumors: Epigenetic landscape and clinical implications
McMurry, H. S., Rivero, J. D., Chen, E. Y.-S., Kardosh, A., Lopez, C. D., & Pegna, G. J. (2024) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2024.101131 · Cited by 11
Salgado, S., Abreu, P. L., Moleirinho, B., Guedes, D. S., Larcombe, L. D., & Azzalin, C. M. (2024) · EMBO Reports · doi:10.1038/s44319-024-00295-3 · Cited by 10
“Since all ALT cells used in this study lack the expression of the chromatin remodeler ATRX (de Nonneville et al, 2022; Lovejoy et al, 2012), PC4 dependency might result from a synthetic interaction between ATRX and PC4 de fi ciencies.”
Heaphy, C. M., & Singhi, A. D. (2023) · Human Pathology · doi:10.1016/j.humpath.2023.01.004 · Cited by 9
Walter, R. M., Majumder, K., & Kalejta, R. F. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012516 · Cited by 9
The molecular landscape of diffuse glioma and prospects for biomarker development
Huse, J. T., & Aldape, K. (2013) · Expert Opinion on Medical Diagnostics · doi:10.1517/17530059.2013.846321 · Cited by 9
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“SP100, PML, FEN1, and CBX3 have been identified as ALT enhancers [46–48]; SP100 is known to induce APBs formation [46] and is downregulated in non-ALT tumors (Figure 4b) while PML, FEN1 and CBX3 are overexpressed.”
BackgroundGonçalves, F. J., de Filippi, M. C. C., da Silva-Lobo, V. L., de Araújo, L. G., da Silva, G. B., Coelho, A. S. G., & Prabhu, A. S. (2016) · Journal of Phytopathology · doi:10.1111/jph.12485 · Cited by 9
Bradfield, A., Button, L., Drury, J. A., Green, D. C., Hill, C. J., & Hapangama, D. K. (2020) · Methods and Protocols · doi:10.3390/mps3030063 · Cited by 9
“TDRD10 is predicted to be associated with telomere maintenance due to its role in DNA repair [100], whilst DUT has been found at the telomeres of telomerase and ALT positive cell lines [110].”
BackgroundTelomeric Repeat-Containing RNA: Biogenesis, Regulation, and FunctionsPreprint
Abreu, P. L., Riva, V., Zardoni, L., & Azzalin, C. M. (2025) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041683 · Cited by 10
2021 World Health Organization Classification of Brain Tumors
Meredith, D. M., & Pisapia, D. J. (2023) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001355 · Cited by 8
“16 As is the case in IDH-mutant astrocytomas, the independent prognostic value of grade 2 versus 3 histologic criteria, if any, is not fully resolved in the modern diagnostic era.”
BackgroundWang, B., Kou, H., Wang, Y., Zhang, Q., Jiang, D., Wang, J., Zhao, Z., Zhou, R., Zhang, M., Sui, L., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07116-4 · Cited by 8
“Subsequently, its impact on ALT formation was elucidated by assessing C-circle formation.”
Biomolecular Condensates in Telomere Maintenance of ALT Cancer Cells
Yu, X., & Zhang, H. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.168951 · Cited by 9
TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells
Moreno, S. P., Fusté, J. M., Kaiser, M., Li, J. S. Z., Nassour, J., Haggblom, C., Denchi, E. L., & Karlseder, J. (2023) · iScience · doi:10.1016/j.isci.2023.106405 · Cited by 8
“29 30–32 Furthermore, ATRX expression in ALT + cells reverses ALT markers, 33,34 suggesting that ATRX is a key suppressor of the ALT mechanism.”
Tichy, E. D., Lee, J., Li, G., Estep, K. N., Johnson, F. B., & Mourkioti, F. (2023) · npj Microgravity · doi:10.1038/s41526-023-00303-1 · Cited by 8
“It has been previously reported that the DNA damage responding proteins, ATRX and DAXX, must be down-regulated for ALT to occur 45 – 48 .”
Epidemiology of Glioblastoma and Trends in Glioblastoma Survivorship
Ostrom, Q. T., Liao, P., Stetson, L. C., & Barnholtz‐Sloan, J. S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-47660-7.00002-1 · Cited by 8
Regulation of Replication Stress in Alternative Lengthening of Telomeres by Fanconi Anaemia Protein
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Dissecting telomere maintenance mechanisms in pediatric glioblastomaPreprint
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“This finding is particularly interesting, since the vast majority of ALT cell lines harbor ATRX mutations and/or show an aberrant ATRX protein expression [30].”
BackgroundAcute irradiation induces a senescence-like chromatin structure in mammalian oocytes
Baumann, C., Zhang, X., Kandasamy, M. K., Mei, X., Chen, S., Tehrani, K. F., Mortensen, L. J., Watford, W. T., Lall, A., & Fuente, R. D. L. (2023) · Communications Biology · doi:10.1038/s42003-023-05641-0 · Cited by 7
“In somatic cells, changes in chromatin motion are an integral component of the cellular response to DNA damage and speci fi c genomic loci exhibit increased mobility over long distances in order to facilitate the repair of double-strand breaks 47 – 52 .”
BackgroundBidzińska, J., Pietro, L. D., Naghshineh, E., Pandini, C., Doria, F., Zaffaroni, N., Gandellini, P., Neidle, S., & Folini, M. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07908-2 · Cited by 8
“…response may contribute to the ability of osteosarcoma cells to cope with G4L exposure It has been reported that the high basal levels of DNA damage that are characteristic of ALT cancer cells [46] are associated with mitochondrial dysfunctions and reactive oxygen species (ROS) production [47, 48].”
Alternative Lengthening of Telomeres: A Prognostic Paradox in Cancer
Sung, J. (2025) · Cells · doi:10.3390/cells14201613 · Cited by 8
“ALT-positive cells exhibit highly heterogeneous telomere lengths—ranging from extremely short to abnormally long—creating a population of highly heterogeneous telomeres prone to replication stress and recombination-mediated instability [7,22–26].”
InfluentialBrown, A., Strickland, L. M., Erman, E. N., Pirozzi, C. J., Low, J., Diplas, B. H., Gibson, E., Shobande, M., Khambati, T., Крылова, М. В., et al. (2026) · Neuro-Oncology · doi:10.1093/neuonc/noaf300 · Cited by 8
A compendium of next-generation patient-derived models for diverse cancers
ElHarouni, D., Al‐Jazrawe, M., Choi, S., Dede, M., Hinoue, T., Misek, S. A., Noh, H., Zanella, L., Tseng, Y.-Y., Francies, H. E., et al. (2026) · Nature · doi:10.1038/s41586-026-10806-y · Cited by 9
“…different datasets: ICGC DCC ESAD-UK 107 , TCGA 108 , the MSKCC– WCM–NYGC HRD project 109 , The Cancer Alliance at NYGC 110 , the Hartwig Medical Foundation (https://www.hartwigmedicalfoundation.nl/en/ data/), ICGC PanCancer Analysis of Whole Genomes 7 , CCLE 2 and other publications 111–116 .”
A Tale of Two States: Pluripotency Regulation of Telomeres
Novo, C. L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.703466 · Cited by 7
“Importantly, ATRX/DAXX mutations are associated with the ALT mechanism, characterized by telomeres with a relaxed heterochromatin state and high TERRA expression (Lovejoy et al., 2012).”
BackgroundHeaphy, C. M., Patel, S., Smith, K., Wondisford, A. R., Lynskey, M. L., O’Sullivan, R. J., Fuhrer, K., Han, X., Seethala, R. R., Liu, T., et al. (2024) · Modern Pathology · doi:10.1016/j.modpat.2024.100651 · Cited by 7
Betlej, G., Ząbek, T., Lewińska, A., Błoniarz, D., Rzeszutek, I., & Wnuk, M. (2022) · Journal of bone oncology · doi:10.1016/j.jbo.2022.100448 · Cited by 7
Telomere maintenance mechanisms in neuroblastoma: New insights and translational implications
Werr, L., Rosswog, C., Bartenhagen, C., George, S. L., & Fischer, M. (2024) · EJC Paediatric Oncology · doi:10.1016/j.ejcped.2024.100156 · Cited by 7
Telomere recombination in normal mammalian cells
Zhdanova, N. S., & Рубцов, Н. Б. (2016) · Russian Journal of Genetics · doi:10.1134/s1022795416010142 · Cited by 6
Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma
Yuan, G., Song, J., Li, N., Song, Q., Li, Y., Du, Y., Wang, X., Jiao, Y., & Wu, L. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01707 · Cited by 7
“H3F3A and DAXX mutations were not found in these samples.”
BackgroundInfluentialSelf-citationAlhendi, A. S. N., & Royle, N. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-77606-w · Cited by 7
Sharaf, R., Montesion, M., Hopkins, J. F., Song, J., Frampton, G. M., & Albacker, L. A. (2022) · Genome Medicine · doi:10.1186/s13073-022-01029-7 · Cited by 7
“Thus, to check if RAD21 or HGF alterations are associated with ALT, we measured TERRA levels from RNA sequencing data, available for 14,074 samples originating from various disease ontologies using TelomereHunter [18].”
BackgroundInfluentialIn Reply: Retention of ATRX and DAXX Expression in Meningiomas
Gill, C. M., Loewenstern, J., Rutland, J. W., Arib, H., Pain, M., Umphlett, M., Kinoshita, Y., McBride, R. B., Bederson, J. B., Donovan, M. J., et al. (2019) · Neurosurgery · doi:10.1093/neuros/nyz504 · Cited by 7
Distinct mechanisms underlying extrachromosomal telomere DNA generation in ALT cancers
Lee, J., Sohn, E. J., Lee, J., Cheng, A. Y., Taglialatela, A., Ciccia, A., & Min, J. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf771 · Cited by 6
Sharaf, R., Jin, D. X., Grady, J. P., Napier, C. E., Ebot, E. M., Frampton, G. M., Albacker, L. A., Thomas, D. M., & Montesion, M. (2023) · npj Genomic Medicine · doi:10.1038/s41525-023-00369-6 · Cited by 6
“Herewesought to investigate the genomic determinants of high telomeric content beyond the canonical ATRX / DAXX alterations within our sarcoma dataset.”
BackgroundInfluentialHost cell interactions of novel antigenic membrane proteins of Mycoplasma agalactiae
Barbosa, M. S., Marques, L. M., Timenetsky, J., Rosengarten, R., Spergser, J., & Chopra‐Dewasthaly, R. (2022) · BMC Microbiology · doi:10.1186/s12866-022-02512-2 · Cited by 6
“For instance, an increased expression of ATRX, which acts on the remodeling of chromatin and is related to the MAPK cascade [74] was observed.”
BackgroundTelomere as a Therapeutic Target in Dedifferentiated Liposarcoma
Alessandrini, I., Percio, S., Naghshineh, E., Zuco, V., Stacchiotti, S., Gronchi, A., Pasquali, S., Zaffaroni, N., & Folini, M. (2022) · Cancers · doi:10.3390/cancers14112624 · Cited by 6
“Western blot analysis revealed that LS-GD-1 cells were characterized by higher levels of basal DNA damage compared to LS-BZ-1 cells (Figure 3B), a feature commonly associated with ALT activity [37].”
BackgroundPrognostic and Predictive Biomarkers for Pancreatic Neuroendocrine Tumors
Hackeng, W. M., Assi, H., Westerbeke, F. H. M., Brosens, L. A. A., & Heaphy, C. M. (2022) · Surgical pathology clinics · doi:10.1016/j.path.2022.05.007 · Cited by 6
Gaspar, T. B., Macedo, S., Sá, A., Soares, M. A., Rodrigues, D. F., Sousa, M., Mendes, N. M., Martins, R. S., Cardoso, L., Borges, I., et al. (2022) · Cancers · doi:10.3390/cancers14163865 · Cited by 6
“A correlation between mutations and the telomerase-independent mechanism of alternative lengthening of telomeres (ALT) was established [21,22], with particular importance to PanNETs [23–25] that rely on this telomere maintenance mechanism (TMM) two times more often (30%) than the overall tumour types (10–15%, on avera…”
BackgroundGenistein suppresses the proliferation of telomerase‐negative cells
Lin, C., Hsieh, M., & Teng, S. (2016) · Food Science & Nutrition · doi:10.1002/fsn3.382 · Cited by 6
“Evidence suggests that ALT is also mediated by epigenetic regulation and gene conversion (Dunham et al. 2000; Lovejoy et al. 2012; O’Sullivan et al. 2014).”
BackgroundCharacterization of the N- terminal domain of Mre11 protein from rice (OsMre11) Oryza sativa
Nair, A., Pillai, V. S., & Chittela, R. K. (2020) · Plant Science · doi:10.1016/j.plantsci.2020.110730 · Cited by 6
Tumor-initiating genetics and therapy drive divergent molecular evolution in IDH-mutant gliomasPreprint
Chowdhury, T., Tesileanu, C. M. S., Kocakavuk, E., Johnson, K. C., Lee, J.-H., Erson-Omay, Z., Heo, C., Aldape, K., Amin, S. B., Anderson, K. J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.11.664189 · Cited by 6
Ding, K., Liu, L., Wang, Y., Sun, B., & Zhang, W. (2025) · European journal of medical research · doi:10.1186/s40001-025-02866-z · Cited by 5
“MKI67 , RAD54L , and PLK1 are potentially associated with telomeres and ALT pathways [38].”
Froney, M. M., Cook, C., Cadiz, A. M., Flinter, K. A., Ledeboer, S. T., Chan, B., Burris, L. E., Hardy, B. P., Pearce, K. H., Wardell, A. C., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00251 · Cited by 6
Exceptional response to the ATR inhibitor, camonsertib, in a patient with ALT+ metastatic melanoma
Ngoi, N. Y. L., Silverman, I. M., Johnson, A., Meng, C., Schonhoft, J. D., Zimmermann, M., Ulanet, D., Kim, H., Torrado, C., Salguero, C., et al. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01025-1 · Cited by 6
Telomere–metabolism–immunity axis in sarcoma: Immune evasion mechanisms and therapeutic strategies
Sung, J., & Kim, J. H. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70504 · Cited by 5
“27 Taken together, knockout models underscore the specificity and functional importance of telomere regulators in orchestrating genomic stability, metabolic reprogramming and immune evasion.”
Mutant ATRX: pathogenesis of ATRX syndrome and cancer
Yuan, K., Tang, Y. H., Ding, Z., Peng, L., Zeng, J., Wu, H., & Yi, Q. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1434398 · Cited by 7
Key rates for the grades and transformation ability of glioma: model simulations and clinical cases
Scribner, E. Y., Hackney, J. R., Machemehl, H. C., Afiouni, R. R., Patel, K. R., & Fathallah‐Shaykh, H. M. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2444-6 · Cited by 5
Bell, W. R., Meeker, A. K., Rizzo, A. J., Rajpara, S., Rosenthal, I. M., Flores‐Bellver, M., Aparicio‐Domingo, S., Zhong, X., Barber, J. R., Joshu, C. E., et al. (2018) · Brain Pathology · doi:10.1111/bpa.12618 · Cited by 5
“To further address the molecular basis of the large, ultra-bright telomere DNA foci, we examined expression of ATRX and DAXX, chromatin remodelling proteins that are frequently mutated or functionally lost in cancers associated with ALT (16, 22).”
BackgroundSelf-citationUsing Transcriptional Signatures to Find Cancer Drivers with LURE
Haan, D., Tao, R., Friedl, V., Anastopoulos, I. N., Wong, C. K., Weinstein, A. S., & Stuart, J. M. (2019) · Pacific Symposium on Biocomputing (PSB) · doi:10.1142/9789811215636_0031 · Cited by 4
Rad21 Haploinsufficiency Prevents ALT-Associated Phenotypes in Zebrafish Brain Tumors
Idilli, A. I., Pazzi, C., Pozzolo, F. D., Roccuzzo, M., & Mione, M. (2020) · Genes · doi:10.3390/genes11121442 · Cited by 5
“In telomerase-positive cells high levels of oncogene-induced telomeric DNA damage could initiate telomere recombination and trigger ALT features [34].”
BackgroundAnalysis of alternative lengthening of telomere markers in BRCA1 defective cells
Kargaran, P. K., Yasaei, H., Anjomani‐Virmouni, S., Mangiapane, G., & Slijepčević, P. (2016) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22386 · Cited by 5
Epigenetics of Human TelomeresPreprint
Bettin, N., Vaurs, M., & Decottignies, A. (2025) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041706 · Cited by 9
It Takes a Village of Chromatin Remodelers to Regulate rDNA Expression
Levesque, M. G., & Picketts, D. J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041772 · Cited by 4
“Indeed, tumors with the alternative lengthening of telomeres (ALT) phenotype are highly correlated with ATRX loss of function, with approximately 90% of ALT tumors harboring ATRX mutation [120].”
Xu, F., Yu, D., Guo, J., Hu, J., Zhao, Y., Jiang, C., Meng, X., Cai, J., & Zhao, Y. (2025) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2025.108537 · Cited by 4
Arakawa, Y., Elloumi, F., Varma, S., Khandagale, P., Jo, U., Kumar, S., Roper, N., Reinhold, W. C., Robey, R. W., Takebe, N., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-24-0100 · Cited by 4
ALT Telomeres Get Together with Nuclear Receptors
Aeby, E., & Lingner, J. (2015) · Cell · doi:10.1016/j.cell.2015.02.006 · Cited by 4
“Whether ATRX loss and nuclear receptor binding to telomeres are sufficient to trigger ALT remains to be tested. telomerase reverse transcriptase (hTERT) gene, or by engaging the ALT pathway to maintain telomeres.”
BackgroundInfluentialInhibition of p53 and ATRX increases telomeric recombination in primary fibroblasts
Udroiu, I., Marinaccio, J., & Sgura, A. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13680 · Cited by 4
Cai, Y., Guo, H., Zhou, J., Zhu, G., Qu, H., Liu, L., Shi, T., Ge, S., & Qu, Y. (2023) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-023-05155-6 · Cited by 4
“FANCF was a DNA repair protein that may operate in a post-replication repair or a cell cycle checkpoint (Lovejoy et al. 2012).”
BackgroundCharacterizing genomic differences of human cancer stratified by the TP53 mutation status
Wang, M., Yang, C., Zhang, X., & Li, X. (2018) · Molecular Genetics and Genomics · doi:10.1007/s00438-018-1416-7 · Cited by 4
Surviving Telomere Attrition with the MiDAS Touch
Flynn, R. L., & Heaphy, C. M. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.08.008 · Cited by 4
Daxx and HIRA go viral – How chromatin remodeling complexes affect DNA virus infection
Mai, J., Nazari, M., Stamminger, T., & Schreiner, S. (2025) · Tumour Virus Research · doi:10.1016/j.tvr.2025.200317 · Cited by 6
ATRX : From Chromatin Remodeling to Disease
Magaña‐Acosta, M., & Valadéz-Graham, V. (2025) · genesis · doi:10.1002/dvg.70031 · Cited by 4
Taylor, E. R., Proctor, B., Vaurs, M., Wu, G., Mahieu, M., Shrestha, S., Morrison, D., Weatherly, L., Brelinsky, S., Raghunandan, M., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117004 · Cited by 3
“7 However, loss of ATRX or DAXX is not sufficient to induce ALT, 8 and how ATRX loss may impact chromatin regulation to contribute to the pathway remains unclear.”
SFPQ directs histone H3.3 deposition to R-loops in DNA repeats to protect genome stability
Ferrando, A., Giaquinto, M., Napolitano, L. M. R., Canarutto, G., Framarini, A., Gambelli, A., Broccia, P. V., Zappone, A., Petti, E., Boncristiani, C., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69479-w · Cited by 4
“3i) 60 .”
Orphan nuclear receptors recruit TRIM28 to promote telomeric H3K9me3 for the ALT pathway
Tsai, C.-T., Gaela, V. M., Hsia, H.-Y., Huang, Y.-C., Shen, Y., & Chen, L. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00760-w · Cited by 5
“…mortal or telomerase-positive cell lines results in reduced histone deposition and telomeric H3K9me3, telomere decompaction, and replication dysfunction, though loss of either protein is not suf fi cient to immediately activate ALT (Li et al, 2019; Lovejoy et al, 2012; O ’ Sullivan et al, 2014).”
Sung, J., & Hwang, K. (2026) · MedComm · doi:10.1002/mco2.70693 · Cited by 3
Meenakshi, S., Maharana, K. C., Nama, L., Vadla, U. K., Dhingra, S., Ravichandiran, V., Murti, K., & Kumar, N. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230809110444 · Cited by 3
“Hence, it is called alternative lengthening of telomeres (ALT), which facilitates genome stability and growth in tumor cells [202, 203].”
Multiple Roles of dXNP and dADD1—Drosophila Orthologs of ATRX Chromatin Remodeler
Melnikova, L. S., & Golovnin, A. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216486 · Cited by 3
“Mutations of the ATRX gene are often found in tumor development, especially in glioma, sarcoma [15], and ALT-positive tumors, although mutations in additional genes are required for ALT activation [166,167].”
BackgroundPierpoint, M., Floyd, W., Wisdom, A. J., Luo, L., Ma, Y., Dickson, B. C., Waitkus, M. S., & Kirsch, D. G. (2025) · iScience · doi:10.1016/j.isci.2025.112357 · Cited by 5
Alternative Lengthening of Telomeres: The Need for ATRX Mutations Is Lineage-Dependent
Udroiu, I., & Sgura, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146765 · Cited by 3
“Moreover, Lovejoy et al. [10] studied many ALT cell lines, investigating both the presence of ALT markers and ATRX alterations.”
Future Directions in the Biology of Neuroendocrine Tumors
Halperin, D. M., Dasari, A. N., & Yao, J. C. (2016) · Pancreas · doi:10.1097/mpa.0000000000000669 · Cited by 3
“Consistent with an important role for telomere biology in NETs, the alterations in DAXX and ATRX observed frequently in pNETs result in an Alternative Lengthening of Telomeres phenotype in which an altered DNA damage response allows for telomerase-independent telomere elongation.(21) Intriguingly, DAXX or ATRX loss in…”
BackgroundTargeting ATR for Cancer Therapy: ATR-Targeted Drug Candidates
Dillon, M. T., & Harrington, K. J. (2018) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-75836-7_5 · Cited by 3
Prognostic biomarkers in pancreatic neuroendocrine tumors
Heaphy, C. M., & VandenBussche, C. J. (2021) · Cancer Cytopathology · doi:10.1002/cncy.22457 · Cited by 4
“These somatic mutations are mutually exclusive and strongly correlate with the alternative lengthening of telomeres (ALT) pathway, a telomeraseindependent telomere maintenance mechanism.(12,13) ATRX and DAXX form a histone chaperone complex that functions to deposit the histone variant H3.”
BackgroundDang, D. D., Rosenblum, J. S., Shah, A. H., Zhuang, Z., & Doucet-O’Hare, T. T. (2023) · Cancers · doi:10.3390/cancers15092511 · Cited by 3
Effects of p53 and ATRX inhibition on telomeric recombination in aging fibroblasts
Udroiu, I., Marinaccio, J., & Sgura, A. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1322438 · Cited by 3
Specificity and sensitivity of ALT ‐associated markers in cancer cells
Udroiu, I., Marinaccio, J., Goffi, R. S., Micheli, E., & Sgura, A. (2025) · FEBS Letters · doi:10.1002/1873-3468.15087 · Cited by 3
“Therefore, the main markers employed to identify ALT cells so far are: Since its discovery in pancreatic neuroendocrine tumors [20], the association between ALT and ATRX and DAXX mutations has been widely demonstrated [21].”
Wang, Z., Wang, Z., Wang, R., Wang, Z., Cao, X., Chen, R., Ma, Z., Liang, S., & Tao, S. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06796-6 · Cited by 3
“Studies have shown that ATRX mutations maintain the stability of chromosome ends through an alternative lengthening of telomere mechanism, increasing the survival and adaptability of tumor cells [51].”
DNA Repair and Telomeres — An Intriguing Relationship
Boutou, E., Vlachodimitropoulos, D., Pappa, V., Stürzbecher, H.-W., & Constantinos, E. (2013) · InTech eBooks · doi:10.5772/56115 · Cited by 3
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Genetic alterations associated with ALTered telomeres
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“The Clynes laboratory is supported through a 472 Children with Cancer UK Paul O’ Gorman Career Development Fellowship (15-202).”
MethodYuan, M., Eberhart, C., Pratilas, C., Blakeley, J., Davis, C., Stojanova, M., Reilly, K. M., Meeker, A., Heaphy, C., & Rodriguez, F. (2022) · bioRxiv · doi:10.1101/2022.02.03.479021
Self-citation
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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