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.

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

“…The RAD51 paralog RAD51C is known to regulate HR in coordination with other RAD51 paralogs as follows: RAD51B, RAD51D, XRCC2, and XRCC3 (18). Biochemical studies show that RAD51C exists in two major complexes, RAD51B/RAD51C/RAD51D/XRCC2 (BCDX2) and the RAD51C/XRCC3 (CX3).…”

“…Biochemical studies show that RAD51C exists in two major complexes, RAD51B/RAD51C/RAD51D/XRCC2 (BCDX2) and the RAD51C/XRCC3 (CX3). Evidence from various studies shows that RAD51C participates in initial and late stages of HR (18). Chicken DT40 and hamster cells lacking RAD51C show reduction in RAD51 foci formation, decreased DSB repair by HR, and elevated chromosomal aberrations (18).…”

“…Evidence from various studies shows that RAD51C participates in initial and late stages of HR (18). Chicken DT40 and hamster cells lacking RAD51C show reduction in RAD51 foci formation, decreased DSB repair by HR, and elevated chromosomal aberrations (18). RAD51C-deficient hamster cells display reduced repair of I-SceI-induced DSBs and increased frequency of long tract gene conversions (LTGC), suggesting the involvement of RAD51C in late stages of recombination (19).…”

“…15 genes (FANCA-C, -D1, -D2, -E-G, -I and -J, and -L-P) have been identified to play a critical role in the FA pathway of ICL repair (18,31,32). Interestingly, three of the FA genes FANCD1, FANCJ, and FANCN are identified as breast cancer susceptibility (BRCA) genes BRCA2, BACH1, and PALB2, respectively (31,32).…”

Incidence of liver abnormalities in Fanconi anemia patients

“…Currently, 15 genes related to FA have been identified [2][3][4], and to date, limited phenotype/genotype correlations have been determined with the exception of cancer incidence in Group D1 [5][6][7].…”