JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity.
The progression of cancer is often associated with genomic instability, which may develop as a result of compromised defense mechanisms responsible for the maintenance of chromosomal integrity. These include defects in telomere preservation, chromosomal segregation, and DNA repair. In this review, we discuss molecular interactions between viral and cellular signaling components, which interfere with DNA repair mechanisms, and possibly contribute to the development of a mutagenic phenotype. Our studies indicate that large T-antigen from the human polyomavirus JC (JCV T-antigen) inhibits homologous recombination directed DNA repair (HRR)-causing accumulation of mutations in the affected cells (JCP 2005, in press). Surprisingly, T-antigen does not operate directly, but utilizes insulin receptor substrate 1 (IRS-1), which is the major signaling molecule for insulin-like growth factor I receptor (IGF-IR). 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 an artificial nuclear localization signal. The interplay described between the IGF-IR signaling system and JCV T-antigen in the process of DNA repair could be relevant, since nearly 90% of the human population is seropositive for JC virus, JCV T-antigen transforms cells in vitro, is tumorigenic in experimental animals, and the presence of JC virus has been shown in an increasing number of biopsies of human cancer.
Center for Neurovirology and Cancer Biology, Temple University, 1900 North 12th Street, Biology Life Science Building, Philadelphia, Pennsylvania 19122, USA. kreiss@temple.edu
Krzysztof
K
Reiss
Kamel
K
Khalili
Antonio
A
Giordano
Joanna
J
Trojanek
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008954:Models, Biological; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction
D000952:Antigens, Polyomavirus Transforming; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1