Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice.
RecA/Rad51 protein family members (Rad51, Rad51b, Rad51c, Rad51d, Xrcc2, and Xrcc3) are essential for DNA repair by homologous recombination, and their role in cancers has been anticipated. Here we provide the first direct evidence for a tumor suppressor function for a member of the Rad51 family. We show 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. 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.
Kuznetsov
Sergey G
SG
Mouse Cancer Genetics Program, Center for Cancer Research, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Haines
Diana C
DC
Martin
Betty K
BK
Sharan
Shyam K
SK
D018266:Adenocarcinoma, Sebaceous / Q000235:genetics; D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051135:Rad51 Recombinase / Q000172:deficiency / Q000235:genetics*; D012626:Sebaceous Gland Neoplasms / Q000235:genetics; D012737:Sex Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D004268:DNA-Binding Proteins; C519208:RAD51C protein, mouse; D016159:Tumor Suppressor Protein p53; D051135:Rad51 Recombinase