Polymerase η suppresses telomere defects induced by DNA damaging agents

Nucleic Acids Res. 2014 Dec 1;42(21):13096-109. doi: 10.1093/nar/gku1030. Epub 2014 Oct 29.

Abstract

Telomeres at chromosome ends are normally masked from proteins that signal and repair DNA double strand breaks (DSBs). Bulky DNA lesions can cause DSBs if they block DNA replication, unless they are bypassed by translesion (TLS) DNA polymerases. Here, we investigated roles for TLS polymerase η, (polη) in preserving telomeres following acute physical UVC exposure and chronic chemical Cr(VI) exposure, which both induce blocking lesions. We report that polη protects against cytotoxicity and replication stress caused by Cr(VI), similar to results with ultraviolet C light (UVC). Both exposures induce ataxia telangiectasia and Rad3-related (ATR) kinase and polη accumulation into nuclear foci and localization to individual telomeres, consistent with replication fork stalling at DNA lesions. Polη-deficient cells exhibited greater numbers of telomeres that co-localized with DSB response proteins after exposures. Furthermore, the genotoxic exposures induced telomere aberrations associated with failures in telomere replication that were suppressed by polη. We propose that polη's ability to bypass bulky DNA lesions at telomeres is critical for proper telomere replication following genotoxic exposures.

Publication types

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

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / analysis
  • Cell Line
  • Cell Line, Transformed
  • Cells, Cultured
  • Chromium / toxicity
  • Chromosome Aberrations
  • DNA Damage*
  • DNA Repair*
  • DNA Replication / drug effects
  • DNA-Directed DNA Polymerase / analysis
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / physiology*
  • Humans
  • Mutagens / toxicity
  • Signal Transduction
  • Telomere / drug effects
  • Telomere / enzymology*
  • Telomere / metabolism
  • Telomere / radiation effects
  • Ultraviolet Rays

Substances

  • Mutagens
  • Chromium
  • chromium hexavalent ion
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA-Directed DNA Polymerase
  • Rad30 protein