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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

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.

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