title: Alterations in DNA repair gene expression under hypoxia: elucidating the mechanisms of hypoxia-induced genetic instability.
abstract: Hypoxia is a common feature of solid tumors and is associated with genetic instability and tumor progression. It has been shown previously that alterations in the expression of DNA repair genes in response to hypoxic stress may account for a proportion of such genetic instability. Here, we demonstrate that the expression of RAD51, a critical mediator of homologous recombination (HR), is repressed by hypoxia in numerous cell lines derived from a wide range of tissues. Repression of this gene by hypoxia occurs in a cell cycle- and hypoxia-inducible factor (HIF)-independent manner, and decreased RAD51 expression was observed to persist during the post-hypoxic period. In addition, decreases in Rad51 expression were correlated with functional impairments in HR repair in hypoxic and post-hypoxic cells. Based on these data, we propose a novel mechanism of hypoxia-induced genetic instability via suppression of the HR pathway in cancer cells within the tumor microenvironment.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA.
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Bindra
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schaffer
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.forename: Jennifer
authors.initials: J
authors.lastname: Woo
authors.forename: Kårstein
authors.initials: K
authors.lastname: Måseide
authors.forename: Matt E
authors.initials: ME
authors.lastname: Roth
authors.forename: Paul
authors.initials: P
authors.lastname: Lizardi
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002469:Cell Separation; D004260:DNA Repair; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D014162:Transfection
chemical_list: D008156:Luciferases; D051135:Rad51 Recombinase