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 language | English |
---|---|
Pages (from-to) | 35-46 |
Number of pages | 12 |
Journal | Journal of Cellular Physiology |
Volume | 206 |
Issue number | 1 |
DOIs | |
State | Published - 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