JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity
Article first published online: 30 JUN 2005
Copyright © 2005 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 206, Issue 2, pages 295–300, February 2006
How to Cite
Reiss, K., Khalili, K., Giordano, A. and Trojanek, J. (2006), JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity. J. Cell. Physiol., 206: 295–300. doi: 10.1002/jcp.20455
- Issue published online: 28 NOV 2005
- Article first published online: 30 JUN 2005
- Manuscript Accepted: 9 MAY 2005
- Manuscript Received: 4 APR 2005
- NIH. Grant Numbers: RO1CA095518, P01 NS36466
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)1. 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. J. Cell. Physiol. 206: 295–300, 2006. © 2005 Wiley-Liss, Inc.