{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T10:05:06Z","timestamp":1774519506656,"version":"3.50.1"},"reference-count":129,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T00:00:00Z","timestamp":1474243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Telomeres are responsible for protecting chromosome ends in order to prevent the loss of coding DNA. Their maintenance is required for achieving immortality by neoplastic cells and can occur by upregulation of the telomerase enzyme or through a homologous recombination-associated process, the alternative lengthening of telomeres (ALT). The precise mechanisms that govern the activation of ALT or telomerase in tumor cells are not fully understood, although cellular origin may favor one of the other mechanisms that have been found thus far in mutual exclusivity. Specific mutational events influence ALT activation and maintenance: a unifying frequent feature of tumors that acquire this phenotype are the recurrent mutations of the Alpha Thalassemia\/Mental Retardation Syndrome X-Linked (ATRX) or Death-Domain Associated Protein (DAXX) genes. This review summarizes the established criteria about this phenotype: its prevalence, theoretical molecular mechanisms and relation with ATRX, DAXX and other proteins (directly or indirectly interacting and resulting in the ALT phenotype).<\/jats:p>","DOI":"10.3390\/genes7090066","type":"journal-article","created":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T10:07:43Z","timestamp":1474279663000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["The Role of ATRX in the Alternative Lengthening of Telomeres (ALT) Phenotype"],"prefix":"10.3390","volume":"7","author":[{"given":"Jo\u00e3o","family":"Amorim","sequence":"first","affiliation":[{"name":"Instituto de Investigac\u0327a\u0303o e Inovac\u0327a\u0303o em Sa\u00fade (i3S), Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto 4200-135, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar da Universidade do Porto, Porto 4050-313, Portugal"}]},{"given":"Gustavo","family":"Santos","sequence":"additional","affiliation":[{"name":"Instituto de Investigac\u0327a\u0303o e Inovac\u0327a\u0303o em Sa\u00fade (i3S), Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto 4200-135, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar da Universidade do Porto, Porto 4050-313, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-1427","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Vinagre","sequence":"additional","affiliation":[{"name":"Instituto de Investigac\u0327a\u0303o e Inovac\u0327a\u0303o em Sa\u00fade (i3S), Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto 4200-135, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar da Universidade do Porto, Porto 4050-313, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-6998","authenticated-orcid":false,"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Instituto de Investigac\u0327a\u0303o e Inovac\u0327a\u0303o em Sa\u00fade (i3S), Universidade do Porto, Porto 4200-135, Portugal"},{"name":"Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto 4200-135, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar da Universidade do Porto, Porto 4050-313, Portugal"},{"name":"Departamento de Patologia e Oncologia, Faculdade de Medicina da Universidade do Porto, Porto 4200-139, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/345458a0","article-title":"Telomeres shorten during ageing of human fibroblasts","volume":"345","author":"Harley","year":"1990","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nrg2763","article-title":"Alternative lengthening of telomeres: Models, mechanisms and implications","volume":"11","author":"Cesare","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0092-8674(93)90234-H","article-title":"An alternative pathway for yeast telomere maintenance rescues EST1-senescence","volume":"73","author":"Lundblad","year":"1993","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/82586","article-title":"Telomere maintenance by recombination in human cells","volume":"26","author":"Dunham","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_6","first-page":"a000661","article-title":"Pml nuclear bodies","volume":"2","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9948","DOI":"10.1128\/MCB.24.22.9948-9957.2004","article-title":"Telomeric DNA in ALT cells is characterized by free telomeric circles and heterogeneous t-loops","volume":"24","author":"Cesare","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/sj.onc.1205058","article-title":"Alternative lengthening of telomeres in mammalian cells","volume":"21","author":"Henson","year":"2002","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/j.ajpath.2011.06.018","article-title":"Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes","volume":"179","author":"Heaphy","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1016\/j.febslet.2010.06.009","article-title":"Assaying and investigating alternative lengthening of telomeres activity in human cells and cancers","volume":"584","author":"Henson","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2217\/17460751.1.1.125","article-title":"Telomerase promoter reprogramming and interaction with general transcription factors in the human mesenchymal stem cell","volume":"1","author":"Serakinci","year":"2006","journal-title":"Regen. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3383","DOI":"10.1038\/sj.onc.1202752","article-title":"Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids","volume":"18","author":"Perrem","year":"1999","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1126\/science.1200609","article-title":"DAXX\/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors","volume":"331","author":"Jiao","year":"2011","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1126\/science.1207313","article-title":"Altered telomeres in tumors with ATRX and DAXX mutations","volume":"333","author":"Heaphy","year":"2011","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lovejoy, C.A., Li, W., Reisenweber, S., Thongthip, S., Bruno, J., de Lange, T., De, S., Petrini, J.H., Sung, P.A., and Jasin, M. (2012). Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002772"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature10833","article-title":"Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma","volume":"482","author":"Schwartzentruber","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10635","DOI":"10.1073\/pnas.1937626100","article-title":"The ATRX syndrome protein forms a chromatin-remodeling complex with DAXX and localizes in promyelocytic leukemia nuclear bodies","volume":"100","author":"Xue","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/370477a0","article-title":"Nucleosome disruption and enhancement of activator binding by a human SW1\/SNF complex","volume":"370","author":"Kwon","year":"1994","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.tcb.2005.12.002","article-title":"DAXX: Death or survival protein?","volume":"16","author":"Salomoni","year":"2006","journal-title":"Trends Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cell.2010.01.003","article-title":"Distinct factors control histone variant H3.3 localization at specific genomic regions","volume":"140","author":"Goldberg","year":"2010","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/bies.20523","article-title":"Physiological relevance of telomeric g-quadruplex formation: A potential drug target","volume":"29","author":"Oganesian","year":"2007","journal-title":"Bioessays"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8112","DOI":"10.1021\/bi00150a002","article-title":"Guanine residues in d(T2AG3) and d(T2G4) form parallel-stranded potassium cation stabilized G-quadruplexes with anti glycosidic torsion angles in solution","volume":"31","author":"Wang","year":"1992","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1093\/nar\/gkp582","article-title":"Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway","volume":"37","author":"Rizzo","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.cell.2010.09.023","article-title":"ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner","volume":"143","author":"Law","year":"2010","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1172\/JCI65634","article-title":"ATRX deficiency induces telomere dysfunction, endocrine defects, and reduced life span","volume":"123","author":"Watson","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7538","DOI":"10.1038\/ncomms8538","article-title":"Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX","volume":"6","author":"Clynes","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.1074\/jbc.M112.411603","article-title":"Alpha thalassemia\/mental retardation syndrome x-linked gene product ATRX is required for proper replication restart and cellular resistance to replication stress","volume":"288","author":"Leung","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7493","DOI":"10.18632\/oncotarget.2115","article-title":"Intratumoral diversity of telomere length in individual neuroblastoma tumors","volume":"6","author":"Pezzolo","year":"2015","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1210\/jc.2007-1840","article-title":"Evaluation of telomere length maintenance mechanisms in adrenocortical carcinoma","volume":"93","author":"Else","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/modpathol.2009.125","article-title":"The alternative lengthening of telomeres phenotype in breast carcinoma is associated with HER-2 overexpression","volume":"22","author":"Subhawong","year":"2009","journal-title":"Mod. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1158\/1078-0432.217.11.1","article-title":"A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas","volume":"11","author":"Henson","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1750-3639.2012.00630.x","article-title":"Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas","volume":"23","author":"Nguyen","year":"2013","journal-title":"Brain Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/modpathol.2013.90","article-title":"The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: A multi-institutional study of 214 astrocytomas","volume":"26","author":"Abedalthagafi","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/S0140-6736(03)12681-5","article-title":"Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme","volume":"361","author":"Jellinek","year":"2003","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1097\/NEN.0b013e3181e576cf","article-title":"Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival","volume":"69","author":"McDonald","year":"2010","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1007\/s00401-014-1348-1","article-title":"Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors","volume":"128","author":"Mangerel","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1038\/modpathol.2013.68","article-title":"Chromophobe hepatocellular carcinoma with abrupt anaplasia: A proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features","volume":"26","author":"Wood","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.humpath.2016.03.015","article-title":"Hi-res telomere FISH reveals intriguing anomalies in germ cell tumors","volume":"54","author":"Shekhani","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4134","DOI":"10.1158\/1078-0432.CCR-08-0099","article-title":"Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma","volume":"14","author":"Villa","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1038\/modpathol.2015.114","article-title":"Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas","volume":"28","author":"Liau","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"928","DOI":"10.2106\/JBJS.G.01390","article-title":"Telomere-maintenance mechanisms in soft-tissue malignant fibrous histiocytomas","volume":"91","author":"Matsuo","year":"2009","journal-title":"J. Bone Jt. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/PAS.0000000000000324","article-title":"Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome","volume":"39","author":"Liau","year":"2015","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8918","DOI":"10.1158\/0008-5472.CAN-06-0273","article-title":"Telomere maintenance mechanisms in liposarcomas: Association with histologic subtypes and disease progression","volume":"66","author":"Costa","year":"2006","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1186\/1471-2407-10-254","article-title":"Prognostic relevance of alt-associated markers in liposarcoma: A comparative analysis","volume":"10","author":"Venturini","year":"2010","journal-title":"BMC Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5347","DOI":"10.1158\/1078-0432.CCR-05-0684","article-title":"Multiple mechanisms of telomere maintenance exist in liposarcomas","volume":"11","author":"Johnson","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/modpathol.2015.67","article-title":"Alternative lengthening of telomeres and loss of ATRX are frequent events in pleomorphic and dedifferentiated liposarcomas","volume":"28","author":"Lee","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1016\/j.humpath.2015.05.019","article-title":"Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas","volume":"46","author":"Liau","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1093\/neuonc\/nos083","article-title":"Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: Expression and prognostic relevance","volume":"14","author":"Venturini","year":"2012","journal-title":"Neuro-oncology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/gcc.20074","article-title":"Divergent patterns of telomere maintenance mechanisms among human sarcomas: Sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing\u2019s sarcomas and osteosarcomas","volume":"41","author":"Ulaner","year":"2004","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_50","first-page":"1759","article-title":"Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma","volume":"63","author":"Ulaner","year":"2003","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1200\/JCO.2004.03.043","article-title":"Telomerase expression predicts unfavorable outcome in osteosarcoma","volume":"22","author":"Sanders","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/j.1349-7006.2008.01063.x","article-title":"Alternative lengthening of telomeres frequently occurs in mismatch repair system-deficient gastric carcinoma","volume":"100","author":"Omori","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E1571","DOI":"10.1210\/jc.2014-1158","article-title":"Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma","volume":"99","author":"Wang","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00401-014-1327-6","article-title":"Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells","volume":"128","author":"Barszczyk","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.lungcan.2010.12.023","article-title":"Telomerase activity in pleural malignant mesotheliomas","volume":"73","author":"Au","year":"2011","journal-title":"Lung Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.1073\/pnas.1303607110","article-title":"Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal","volume":"110","author":"Killela","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s00401-013-1163-0","article-title":"Tert promoter mutations in primary and secondary glioblastomas","volume":"126","author":"Nonoguchi","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/ijc.30057","article-title":"The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism","volume":"139","author":"Batista","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s00401-013-1195-5","article-title":"Distribution of tert promoter mutations in pediatric and adult tumors of the nervous system","volume":"126","author":"Koelsche","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S1470-2045(13)70110-4","article-title":"Methylation of the TERT promoter and risk stratification of childhood brain tumours: An integrative genomic and molecular study","volume":"14","author":"Choufani","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/nature14980","article-title":"Telomerase activation by genomic rearrangements in high-risk neuroblastoma","volume":"526","author":"Peifer","year":"2015","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"67","DOI":"10.7150\/jca.3965","article-title":"Telomerase-independent paths to immortality in predictable cancer subtypes","volume":"3","author":"Durant","year":"2012","journal-title":"J. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1159\/000167814","article-title":"Telomere length maintenance\u2014An alternative mechanism","volume":"122","author":"Royle","year":"2008","journal-title":"Cytogenet. Genome Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1093\/nar\/gkh691","article-title":"Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells","volume":"32","author":"Bailey","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"727","DOI":"10.18632\/aging.100206","article-title":"Telomere sister chromatid exchange and the process of aging","volume":"10","author":"Blagoev","year":"2010","journal-title":"Aging"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/0092-8674(95)90287-2","article-title":"Mutations in a putative global transcriptional regulator cause x-linked mental retardation with a-thalassemia (ATR-X syndrome)","volume":"80","author":"Gibbons","year":"1995","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1093\/hmg\/5.12.1899","article-title":"ATRX encodes a novel member of the SNF2 family of proteins: Mutations point to a common mechanism underlying the ATR-X syndrome","volume":"5","author":"Picketts","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/embor.2009.218","article-title":"Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain","volume":"10","author":"Otani","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nature05987","article-title":"DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA","volume":"448","author":"Ooi","year":"2007","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"11939","DOI":"10.1073\/pnas.0704057104","article-title":"Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX","volume":"104","author":"Argentaro","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1093\/nar\/gkl295","article-title":"Identification of multiple distinct SNF2 subfamilies with conserved structural motifs","volume":"34","author":"Flaus","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1101\/gad.566910","article-title":"The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3","volume":"24","author":"Drane","year":"2010","journal-title":"Genes Dev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"14075","DOI":"10.1073\/pnas.1008850107","article-title":"DAXX is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres","volume":"107","author":"Lewis","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13983","DOI":"10.1073\/pnas.96.24.13983","article-title":"Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes","volume":"96","author":"McDowell","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/74191","article-title":"Mutations in ATRX, encoding a SWI\/SNF-like protein, cause diverse changes in the pattern of DNA methylation","volume":"24","author":"Gibbons","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_76","first-page":"1235","article-title":"A possible involvement of TIFIa and TIF1, in the epigenetic control of transcription by nuclear receptor","volume":"10","author":"Nielsen","year":"1996","journal-title":"EMBO Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1073\/pnas.0608056104","article-title":"Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation","volume":"104","author":"Nan","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature722","article-title":"Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9","volume":"416","author":"Nielsen","year":"2002","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nsmb.2070","article-title":"Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin","volume":"18","author":"Eustermann","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.tibs.2013.06.011","article-title":"The chromatin remodeller ATRX: A repeat offender in human disease","volume":"38","author":"Clynes","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4412","DOI":"10.1172\/JCI63765","article-title":"Compromised genomic integrity impedes muscle growth after ATRX inactivation","volume":"122","author":"Huh","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"328ra28","DOI":"10.1126\/scitranslmed.aac8228","article-title":"ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma","volume":"8","author":"Koschmann","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Clynes, D., Jelinska, C., Xella, B., Ayyub, H., Taylor, S., Mitson, M., Bachrati, C.Z., Higgs, D.R., and Gibbons, R.J. (2014). ATRX dysfunction induces replication defects in primary mouse cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092915"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cell.2010.10.021","article-title":"ATRX: Put me on repeat","volume":"143","author":"Whitehouse","year":"2010","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1128\/MCB.25.7.2708-2721.2005","article-title":"Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11\/RAD50\/NBS1 complex","volume":"25","author":"Jiang","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/ncb1867","article-title":"Telomere recombination requires the MUS81 endonuclease","volume":"11","author":"Zeng","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"34802","DOI":"10.1074\/jbc.M404750200","article-title":"Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact at sites of stalled replication forks","volume":"279","author":"Robison","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cell.2006.09.034","article-title":"The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres","volume":"127","author":"Verdun","year":"2006","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4692","DOI":"10.1093\/nar\/gki777","article-title":"Saccharomyces cerevisiae mre11 is a high-affinity G4 DNA-binding protein and a G-rich DNA-specific endonuclease: Implications for replication of telomeric DNA","volume":"33","author":"Ghosal","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.cell.2011.12.028","article-title":"Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer","volume":"148","author":"Hu","year":"2012","journal-title":"Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1593\/neo.10180","article-title":"TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression","volume":"12","author":"Bilsland","year":"2010","journal-title":"Neoplasia"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.mrfmmm.2012.11.006","article-title":"Alternative mechanisms of telomere lengthening: Permissive mutations, DNA repair proteins and tumorigenic progression","volume":"743\u2013744","author":"Gocha","year":"2013","journal-title":"Mutat. Res."},{"key":"ref_93","first-page":"4175","article-title":"Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body","volume":"59","author":"Yeager","year":"1999","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6400","DOI":"10.1158\/1078-0432.CCR-11-3150","article-title":"Molecular pathways: Understanding the role of Rad52 in homologous recombination for therapeutic advancement","volume":"18","author":"Lok","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1128\/MCB.24.6.2344-2351.2004","article-title":"Rad51-dependent break-induced replication in yeast","volume":"24","author":"Davis","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0092-8674(04)00337-X","article-title":"Telomere maintenance requires the RAD51D recombination\/repair protein","volume":"117","author":"Tarsounas","year":"2004","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nsmb1259","article-title":"The SMC5\/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins","volume":"14","author":"Potts","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/nbt.1587","article-title":"DNA c-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity","volume":"27","author":"Henson","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nature09399","article-title":"Purified human BRCA2 stimulates RAD51-mediated recombination","volume":"467","author":"Jensen","year":"2010","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1038\/onc.2012.391","article-title":"RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination","volume":"32","author":"Lok","year":"2013","journal-title":"Oncogene"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1158\/0008-5472.CAN-06-3672","article-title":"XRCC3 and NBS1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells","volume":"67","author":"Compton","year":"2007","journal-title":"Cancer Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1101\/gad.1346005","article-title":"Shelterin: The protein complex that shapes and safeguards human telomeres","volume":"19","year":"2005","journal-title":"Genes Dev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1083\/jcb.200703020","article-title":"Lack of TRF2 in ALT cells causes pml-dependent p53 activation and loss of telomeric DNA","volume":"179","author":"Foxon","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1083\/jcb.201207189","article-title":"Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells","volume":"199","author":"Conomos","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Gocha, A.R., Acharya, S., and Groden, J. (2014). WRN loss induces switching of telomerase-independent mechanisms of telomere elongation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093991"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1093\/hmg\/11.25.3135","article-title":"The bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis","volume":"11","author":"Stavropoulos","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/990147","article-title":"The RCAF complex mediates chromatin assembly during DNA replication and repair","volume":"402","author":"Tyler","year":"1999","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0092-8674(03)01064-X","article-title":"Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis","volume":"116","author":"Tagami","year":"2004","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nsmb.2754","article-title":"Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1","volume":"21","author":"Arnoult","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1101\/gad.1839909","article-title":"The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks","volume":"23","author":"Bansbach","year":"2009","journal-title":"Genes Dev."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1101\/gad.178459.111","article-title":"SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication","volume":"26","author":"Betous","year":"2012","journal-title":"Genes Dev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"14864","DOI":"10.1073\/pnas.1510750112","article-title":"SMARCAL1 maintains telomere integrity during DNA replication","volume":"112","author":"Poole","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1093\/nar\/gkm738","article-title":"Replication protein a prevents accumulation of single-stranded telomeric DNA in cells that use alternative lengthening of telomeres","volume":"35","author":"Grudic","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"395","DOI":"10.18632\/aging.100308","article-title":"Depletion of Ku70\/80 reduces the levels of extrachromosomal telomeric circles and inhibits proliferation of ALT cells","volume":"3","author":"Li","year":"2011","journal-title":"Aging"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/onc.2008.458","article-title":"FEN1 contributes to telomere stability in ALT-positive tumor cells","volume":"28","author":"Saharia","year":"2009","journal-title":"Oncogene"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrm1546","article-title":"P53: Traffic cop at the crossroads of DNA repair and recombination","volume":"6","author":"Sengupta","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/carcin\/bgn050","article-title":"Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer","volume":"29","author":"Perera","year":"2008","journal-title":"Carcinogenesis"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"6473","DOI":"10.1158\/0008-5472.CAN-06-0910","article-title":"Association of mutant TP53 with alternative lengthening of telomeres and favorable prognosis in glioma","volume":"66","author":"Chen","year":"2006","journal-title":"Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nrgastro.2012.9","article-title":"Well-differentiated pancreatic neuroendocrine tumors: From genetics to therapy","volume":"9","author":"Edil","year":"2012","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/S0002-9440(10)65495-8","article-title":"Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization","volume":"155","author":"Speel","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/S0002-9440(10)64624-X","article-title":"Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells","volume":"157","author":"Perren","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S1097-2765(04)00081-4","article-title":"Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus","volume":"13","author":"Hughes","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ccr.2005.08.008","article-title":"The AKT-mTOR tango and its relevance to cancer","volume":"8","author":"Hay","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.jamcollsurg.2014.01.001","article-title":"Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor liver metastases","volume":"218","author":"Dogeas","year":"2014","journal-title":"J. Am. Coll. Surg."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"29714","DOI":"10.1038\/srep29714","article-title":"TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes","volume":"6","author":"Vinagre","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"16543","DOI":"10.18632\/oncotarget.3846","article-title":"ATRX represses alternative lengthening of telomeres","volume":"6","author":"Napier","year":"2015","journal-title":"Oncotarget"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/sj.leu.2402962","article-title":"Lack of telomerase activity in human mesenchymal stem cells","volume":"17","author":"Zimmermann","year":"2003","journal-title":"Leukemia"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.ccell.2015.08.003","article-title":"Loss of ATRX suppresses resolution of telomere cohesion to control recombination in ALT cancer cells","volume":"28","author":"Ramamoorthy","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1126\/science.1257216","article-title":"Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors","volume":"347","author":"Flynn","year":"2015","journal-title":"Science"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/7\/9\/66\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:31:10Z","timestamp":1760211070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/7\/9\/66"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,19]]},"references-count":129,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2016,9]]}},"alternative-id":["genes7090066"],"URL":"https:\/\/doi.org\/10.3390\/genes7090066","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,19]]}}}