T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51

Joanna Trojanek, Sidney Croul, Thu Ho, Jin Ying Wang, Armine Darbinyan, Michal Nowicki, Luis Del Valle, Tomasz Skorski, Kamel Khalili, Krzysztof Reiss

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

JC polyomavirus (JCV), which infects 90% of the human population, is detectable in human tumors. Its early protein, JCV T-antigen, transforms cells in vitro and is tumorigenic in experimental animals. Although T-antigen-mediated transformation in volves genetic alterations of the affected cells, the mechanism underlying this genomic instability is not known. We show that JCV T-antigen inhibits homologous recombination DNA repair (HRR), which results in an accumulation of mutations. T-antigen does not operate directly but utilizes a cytosolic molecule, insulin receptor substrate 1 (IRS-1). Following T-antigen-mediated nuclear translocation, IRS-1 binds Rad51 at the site of damaged DNA. This T-antigen-mediated inhibition of HRR does not function in cells lacking IRS-1, and can be reproduced in the absence of T-antigen by IRS-1 with artificial nuclear localization signal. Our observations define a new mechanism by which viral protein utilizes cytosolic molecule to inhibit faithful DNA repair, and suggest how polyomaviruses could compromise stability of the genome.

Original languageEnglish
Pages (from-to)35-46
Number of pages12
JournalJournal of Cellular Physiology
Volume206
Issue number1
DOIs
StatePublished - Jan 2006

Keywords

  • Animals
  • Antigens, Viral, Tumor/metabolism
  • Base Sequence
  • Cell Nucleus/metabolism
  • Cells, Cultured
  • DNA Damage
  • DNA Repair
  • Humans
  • Insulin Receptor Substrate Proteins
  • JC Virus/metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Phosphoproteins/metabolism
  • Rad51 Recombinase/metabolism
  • Receptor, Insulin/metabolism
  • Recombination, Genetic
  • Sequence Alignment

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