Overexpression of mammalian Rad51 does not stimulate tumorigenesis while a dominant-negative Rad51 affects centrosome fragmentation, ploidy and stimulates tumorigenesis, in p53-defective CHO cells.
Rad51 protein plays a pivotal role in homologous recombination (HR), which is involved in double-strand break repair and in genome maintenance. Despite interactions with tumor suppressor proteins, the role of mammalian Rad51 and more generally of HR in tumor prevention is not clearly established. Indeed, both high and low frequencies of HR as well as high and low levels of RAD51 expression have been reported in tumors and in precancerous conditions. To address the question of the impact of HR on tumorigenesis, we used Chinese hamster ovary (CHO) p53-defective cell lines overexpressing the mouse MmRAD51, which stimulates HR (we name these lines: Hyper-rec lines). In parallel, we used CHO cell lines expressing a RAD51 dominant-negative form that specifically inhibits gene conversion without affecting cell viability (Hypo-rec lines). These different lines were injected into nude mice to measure their tumorigenicity. Hypo-rec lines generated a higher frequency of tumors, which also exhibited faster growth, compared to control and Hyper-rec lines. Consistent with tumorigenicity, Hypo-rec cells exhibit spontaneous centrosome duplication defects and aneuploidy. These results are the first direct evidence of involvement of RAD51 in tumor repression.
UMR CEA/CNRS 217, France.
Pascale
P
Bertrand
Sarah
S
Lambert
Christophe
C
Joubert
Bernard S
BS
Lopez
D000782:Aneuploidy; D000818:Animals; D016466:CHO Cells; D002455:Cell Division; D018385:Centrosome / Q000378:metabolism / Q000473:pathology*; D006224:Cricetinae; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005785:Gene Conversion; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse