Kuznetsov Sergey G, Haines Diana C, Martin Betty K, Sharan Shyam K
Mouse Cancer Genetics Program, Center for Cancer Research, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Cancer Res. 2009 Feb 1;69(3):863-72. doi: 10.1158/0008-5472.CAN-08-3057. Epub 2009 Jan 20.
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.
RecA/Rad51蛋白家族成员（Rad51、Rad51b、Rad51c、Rad51d、Xrcc2和Xrcc3）对于通过同源重组进行的DNA修复至关重要，它们在癌症中的作用也已被人们所预期。在此，我们首次为Rad51家族成员的肿瘤抑制功能提供了直接证据。我们发现，Rad51c缺陷会导致早期胚胎致死，而在Trp53基因缺失的背景下这种致死效应会延迟。为了揭示Rad51c在肿瘤发生中的作用，我们利用了Rad51c和Trp53都紧密位于小鼠11号染色体上这一事实。我们构建了双杂合（DH）小鼠，其携带的两个基因的突变等位基因分别位于不同染色体（DH-trans）或同一染色体上（DH-cis），后者可通过杂合性缺失导致两个基因的野生型等位基因缺失。与DH-cis小鼠不同，DH-trans小鼠发生肿瘤的潜伏期和肿瘤谱与Trp53杂合小鼠相似。令人惊讶的是，DH-cis小鼠中的Rad51c突变促进了特殊皮脂腺肿瘤的发生，并抑制了Trp53突变特征性的肿瘤。此外，DH-cis雌性小鼠发生肿瘤的时间明显早于其他任何组。
