抄録
Rad51C is a member of Rad51 paralogs conserved in vertebrates and plays a role in homologous recombination repair. The functional analysis of Rad51 paralogs has been exerted mainly in knocked out DT40 cells, mutated CHO cells and/or knockout mice. Hypersensitivities to radiation and inter-strand cross-linking agents, a reduction in homologous recombination and increased chromosomal aberrations have been reported. In addition, recent reports have shown that Rad51C is required for Holliday junction resolution and Rad51 paralogs are required for telomere maintenance. These findings suggest that Rad51 paralogs play crucial roles in DNA repair and maintenance of chromosomal integrity. We generated the human colon cancer cell line HCT116 harboring Rad51C mutation by gene targeting. They showed hypersensitivities to radiation and inter-strand cross-linking agents, and increases in chromosomal aberrations and aneploidy as observed in DT40 and CHO mumant cells. Furthermore, the cells showed slow growth, which was caused by decreased activities of cyclin E and cyclin A. An increase in p21 and phosphorylation of p53 at serine 15 were also observed. As the increase in p21 was cancelled by the addition of caffeine, G1 checkpoint appeared to be activated by the ATM/ATR-p53-p21 pathway. Furthermore, the ectopic expression of cdk2 reversed increased aneuploidy. Taken together, Rad51C dysfunction leads to activation of G1 checkpoint with reduced cdk2 activity, which may cause aneuploidy.
