Cell and Tissue Signaling

Tuesday, October 18, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP218) Dysregulation of DNA repair genes in hypoxia.

Glazer, Peter*,1, Bindra, Ranjit1, 1 Department of Therapeutic Radiology, New Haven, CT, USA

ABSTRACT- There is an emerging concept that the dysregulation of critical DNA repair pathways due to microenvironmental stresses such as hypoxia can contribute to genetic instability and tumor progression in cancer cells. Given the complex gene expression changes observed under hypoxia, we are investigating whether actual decreases in the expression of DNA repair genes can account for a proportion of hypoxia-induced genetic instability. Intriguingly, we have detected novel alterations in the expression of several genes involved in the homologous recombination (HR) pathway of double-strand break (DSB) repair, including Rad51 and Brca1. In contrast, the expression of several key proteins involved in the non-homologous end-joining (NHEJ) pathway of DSB repair are not altered by hypoxia, indicating that this pathway may remain intact in hypoxic cells. Substantial decreases in HR repair were observed in hypoxic compared to normoxic cells using both extra- and intra-chromosomally-based DNA repair assays, suggesting that the observed alterations in DNA repair gene expression have functional consequences. Based on these findings, we propose a novel mechanism of genetic instability in the tumor microenvironment mediated by hypoxia-induced dysregulation of DSB repair in cancer cells. Specifically, hypoxia-mediated decreases in critical HR genes and consequently diminished HR may lead to genetic instability by shifting the balance between the high-fidelity HR and the error-prone NHEJ pathways of DSB repair. As both hypoxia and DNA repair gene expression independently have been shown to play critical roles in the response to chemotherapy and ionizing radiation, further elucidation of this phenomenon likely will facilitate the development of improved treatment modalities.

Key words: hypoxia, DNA repair, genetic instability, Rad51

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2005 RRS