RAD51C: a novel cancer susceptibility gene is linked to Fanconi anemia and breast cancer

Abstract

Germline mutations in many of the genes that are involved in homologous recombination (HR)-mediated DNA double-strand break repair (DSBR) are associated with various human genetic disorders and cancer. RAD51 and RAD51 paralogs are important for HR and in the maintenance of genome stability. Despite the identification of five RAD51 paralogs over a decade ago, the molecular mechanism(s) by which RAD51 paralogs regulate HR and genome maintenance remains obscure. In addition to the known roles of RAD51C in early and late stages of HR, it also contributes to activation of the checkpoint kinase CHK2. One recent study identifies biallelic mutation in RAD51C leading to Fanconi anemia-like disorder. Whereas a second study reports monoallelic mutation in RAD51C associated with increased risk of breast and ovarian cancer. These reports show RAD51C is a cancer susceptibility gene. In this review, we focus on describing the functions of RAD51C in HR, DNA damage signaling and as a tumor suppressor with an emphasis on the new roles of RAD51C unveiled by these reports.

Fig. 1.

Alternative mechanisms of DNA DSBR by HR. DSBs can be repaired by two alternative pathways of HR such as SDSA and DSBR. In both the pathways, DSB ends are processed by nucleolytic resection to generate 3′ ssDNA, which serves as a substrate for HR machinery to engage in homologous search and strand invasion. DNA synthesis will be initiated from the invaded strand in D-loop structures. In the SDSA pathway, the nascent strand will be displaced from the D-loop and anneals to the second end of the broken DNA, followed by gap filling and ligation DSBR is completed. In the DSBR pathway, extension of D-loop by nascent strand synthesis captures the second end to generate double-HJ structures. After the gap repair and ligation, HJs are resolved by resolvases to result in either non-crossover (black triangles) or crossover products (gray triangles).

Fig. 2.

A model for the role of RAD51C in DSBR by HR, ICL repair and checkpoint activation. (a) In response to DSBs, RAD51C localizes to DSBs in an ATM/ATR-dependent manner. (b) RAD51C controls RAD51 recruitment to the processed DSB ends in the initial stages of HR. (c) RAD51C also regulates resolution of recombination intermediates at the later stages. (d) RAD51C is required for CHK2 activation and checkpoint function. (e) FA core complex is activated and recruited by ATR kinase in response to ICL lesion. (f) RAD51C appears to be part of the ICL repair complex contributing to the ICL repair. Defect in the RAD51C HR function and checkpoint regulation may cause FA-like disorder and cancer.