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

PLoS Genet. 2012;8(7):e1002772. doi: 10.1371/journal.pgen.1002772. Epub 2012 Jul 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Repair / genetics
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Genomic Instability
  • HeLa Cells
  • Histones* / genetics
  • Histones* / metabolism
  • Homologous Recombination
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Signal Transduction
  • Telomerase / genetics
  • Telomere / genetics*
  • Telomere / metabolism
  • Telomere Homeostasis / genetics*
  • X-linked Nuclear Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • DAXX protein, human
  • Histones
  • Nuclear Proteins
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein