Examining the Role of Rad51c as a Tumor Suppressor

Division Of Basic Sciences - Nci

Investigators

Abstract

To study the function of RAD51C in mice and examine whether there is any functional redundancy between RAD51C and other paralogs in mammals, we have generated mutations in the Rad51c gene. We have shown that Rad51c deficiency leads to early embryonic lethality, which can be delayed on a Trp53-null background. To uncover the role of Rad51c in tumorigenesis, we have exploited the fact that Rad51c and Trp53 are both closely located on the mouse chromosome 11. We have generated double heterozygous (DH) mice carrying mutant alleles of both genes either on different (DH-trans) or on the same chromosome (DH-cis), the latter allowing for a deletion of wild-type alleles of both genes by loss of heterozygosity (LOH). DH-trans mice, in contrast to DH-cis, developed tumors with latency and spectrum similar to Trp53 heterozygous mice. Strikingly, Rad51c mutation in DH-cis mice promoted the development of tumors of specialized sebaceous glands and suppressed tumors characteristic of Trp53 mutation. In addition, DH-cis, females developed tumors significantly earlier than any other group.In summary, our results suggest that Rad51c functions as a tumor suppressor in mice. This is the first demonstration of a role in tumorigenesis for any Rad51 family member in mice. Similar studies may reveal unexpected tissue-specific effects for other Rad51 family members. Our future studies will be focused on examining the role of Rad51c in human tumors and on understanding the tissue-specific functions of Rad51c in epithelial tissues.