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

Courtney A. Lovejoy, Wendi Li, Steven Reisenweber, Supawat Thongthip, Joanne Bruno, Titia de Lange, Saurav De, John H. J. Petrini, Patricia A. Sung, Maria Jasin, Joseph Rosenbluh, Yaara Zwang, Barbara A. Weir, Charlie Hatton, Elena Ivanova, Laura Macconaill, Megan Hanna, William C. Hahn, Neal F. Lue, Roger R. ReddelYuchen Jiao, Kenneth Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Alan K. Meeker

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320 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002772
Pages (from-to)1-16
Number of pages16
JournalPLoS Genetics
Volume8
Issue number7
DOIs
Publication statusPublished - Jul 2012
Externally publishedYes

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