T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51.
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 involves 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. (c) 2005 Wiley-Liss, Inc.
Trojanek
Joanna
J
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Biology Life Science Building, Philadelphia, Pennsylvania 19122, USA.
Croul
Sidney
S
Ho
Thu
T
Wang
Jin Ying
JY
Darbinyan
Armine
A
Nowicki
Michal
M
Del Valle
Luis
L
Skorski
Tomasz
T
Khalili
Kamel
K
Reiss
Krzysztof
K
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007577:JC Virus / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D011995:Recombination, Genetic; D016415:Sequence Alignment
D000957:Antigens, Viral, Tumor; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011972:Receptor, Insulin; D051135:Rad51 Recombinase