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Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.

TitleLoss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.
Publication TypeJournal Article
Year of Publication2012
AuthorsLovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JHJ, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, Hanna M, Hahn WC, Lue NF, Reddel RR, Jiao Y, Kinzler K, Vogelstein B, Papadopoulos N, Meeker AK
Corporate AuthorsALT Starr Cancer Consortium
JournalPLoS Genet
Volume8
Issue7
Paginatione1002772
Date Published2012
ISSN1553-7404
KeywordsAdaptor Proteins, Signal Transducing, Chromatin Assembly and Disassembly, DNA Breaks, Double-Stranded, DNA Damage, DNA Helicases, DNA Repair, G2 Phase Cell Cycle Checkpoints, Genomic Instability, HeLa Cells, Histones, Homologous Recombination, Humans, Nuclear Proteins, Signal Transduction, Telomerase, Telomere, Telomere Homeostasis, X-linked Nuclear Protein
Abstract

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.

DOI10.1371/journal.pgen.1002772
Alternate JournalPLoS Genet
PubMed ID22829774
PubMed Central IDPMC3400581
Grant ListR37 CA043460 / CA / NCI NIH HHS / United States
R37 GM059413 / GM / NIGMS NIH HHS / United States
R13 CA162528 / CA / NCI NIH HHS / United States
R01 GM049046 / GM / NIGMS NIH HHS / United States
F32GM090437 / GM / NIGMS NIH HHS / United States
CA076027 / CA / NCI NIH HHS / United States
R37 GM049046 / GM / NIGMS NIH HHS / United States
R01 AG023145 / AG / NIA NIH HHS / United States
GM049046 / GM / NIGMS NIH HHS / United States
F32 GM090437 / GM / NIGMS NIH HHS / United States
R01 CA076027 / CA / NCI NIH HHS / United States
R01 GM056888 / GM / NIGMS NIH HHS / United States

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