title: Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability.
abstract: RAD51, a key protein in the homologous recombinational DNA repair (HRR) pathway, is the major strand-transferase required for mitotic recombination. An important early step in HRR is the formation of single-stranded DNA (ss-DNA) coated by RPA (a ss-DNA-binding protein). Displacement of RPA by RAD51 is highly regulated and facilitated by a number of different proteins known as the 'recombination mediators'. To assist these recombination mediators, a second group of proteins also is required and we are defining these proteins here as 'recombination co-mediators'. Defects in either recombination mediators or co-mediators, including BRCA1 and BRCA2, lead to impaired HRR that can genetically be complemented for (i.e. suppressed) by overexpression of RAD51. Defects in HRR have long been known to contribute to genomic instability leading to tumor development. Since genomic instability also slows cell growth, precancerous cells presumably require genomic re-stabilization to gain a growth advantage. RAD51 is overexpressed in many tumors, and therefore, we hypothesize that the complementing ability of elevated levels of RAD51 in tumors with initial HRR defects limits genomic instability during carcinogenic progression. Of particular interest, this model may also help explain the high frequency of TP53 mutations in human cancers, since wild-type p53 represses RAD51 expression.
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA. dschild@lbl.gov
authors: David
authors: D
authors: Schild
authors: Claudia
authors: C
authors: Wiese
mesh_terms: D000818:Animals; D004260:DNA Repair; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D011995:Recombination, Genetic
chemical_list: D051135:Rad51 Recombinase