Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of Telomeres pathway Journal Article
| 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. |
| Article Title: | Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of Telomeres pathway |
| 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. © 2012 Lovejoy et al. |
| Keywords: | signal transduction; controlled study; unclassified drug; gene mutation; human cell; sequence analysis; genetic analysis; telomere; dna damage; gene; homologous recombination; dna repair; nuclear protein; embryo; protein depletion; hela cells; telomerase; nuclear proteins; cancer genetics; gene rearrangement; genomic instability; adaptor proteins, signal transducing; dna breaks, double-stranded; double stranded dna break; fetus; gene dosage; karyotype; histones; dna helicases; chromatin assembly and disassembly; cell immortalization; micronucleus; daxx protein; protein atrx; g2 phase cell cycle checkpoints; atrx gene; telomere homeostasis; alternative lengthening of telomere pathway; daxx gene; g2 phase cell cycle checkpoint; h3f3a gene; m phase cell cycle checkpoint |
| Journal Title: | PLoS Genetics |
| Volume: | 8 |
| Issue: | 7 |
| ISSN: | 1553-7390 |
| Publisher: | Public Library of Science |
| Date Published: | 2012-07-01 |
| Start Page: | e1002772 |
| Language: | English |
| DOI: | 10.1371/journal.pgen.1002772 |
| PROVIDER: | scopus |
| PMCID: | PMC3400581 |
| PUBMED: | 22829774 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2012" - "Source: Scopus" |
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