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Molecular and Cellular Biology, November 2003, p. 7510-7524, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7510-7524.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of the Insulin-Like Growth Factor I/Insulin Receptor Substrate 1 Axis in Rad51 Trafficking and DNA Repair by Homologous Recombination

Joanna Trojanek,1,2 Thu Ho,1 Luis Del Valle,1 Michal Nowicki,3 Jin Ying Wang,1 Adam Lassak,1 Francesca Peruzzi,1 Kamel Khalili,1 Tomasz Skorski,3 and Krzysztof Reiss1*

Center for Neurovirology and Cancer Biology,1 Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122,3 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland2

Received 28 April 2003/ Returned for modification 19 June 2003/ Accepted 29 July 2003

The receptor for insulin-like growth factor I (IGF-IR) controls normal and pathological growth of cells. DNA repair pathways represent an unexplored target through which the IGF-IR signaling system might support pathological growth leading to cellular transformation. However, this study demonstrates that IGF-I stimulation supports homologous recombination-directed DNA repair (HRR). This effect involves an interaction between Rad51 and the major IGF-IR signaling molecule, insulin receptor substrate 1 (IRS-1). The binding occurs within the cytoplasm, engages the N-terminal domain of IRS-1, and is attenuated by IGF-I-mediated IRS-1 tyrosine phosphorylation. In the absence of IGF-I stimulation, or if mutated IGF-IR fails to phosphorylate IRS-1, localization of Rad51 to the sites of damaged DNA is diminished. These results point to a direct role of IRS-1 in HRR and suggest a novel role for the IGF-IR/IRS-1 axis in supporting the stability of the genome.

* Corresponding author. Mailing address: Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 North 12th St., Biology Life Science Building, Philadelphia, PA 19122. Phone: (215) 204-6345. Fax: (215) 204-0679. E-mail: kreiss{at}temple.edu.

Molecular and Cellular Biology, November 2003, p. 7510-7524, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7510-7524.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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