Cao Liu, Kim Sangsoo, Xiao Cuiying, Wang Rui-Hong, Coumoul Xavier, Wang Xiaoyan, Li Wen Mei, Xu Xiao Ling, De Soto Joseph A, Takai Hiroyuki, Mai Sabine, Elledge Stephen J, Motoyama Noboru, Deng Chu-Xia
Genetics of Development and Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
EMBO J. 2006 May 17;25(10):2167-77. doi: 10.1038/sj.emboj.7601115. Epub 2006 May 4.
BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1(delta11/delta11)) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca1(delta11/delta11)p53+/- mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca1(delta11/delta11) mice to escape from embryonic lethality. Compared to Brca1(delta11/delta11)p53+/- mice, lifespan of Brca1(delta11/delta11)Chk2-/- mice was remarkably extended. Analysis of Brca1(delta11/delta11)Chk2-/- mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(delta11/delta11)Chk2-/- female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer.
BRCA1是一个确保基因组完整性的检查点和DNA损伤修复基因。我们之前已经表明，缺乏全长Brca1的小鼠（Brca1(delta11/delta11)）在胚胎发育期间死亡。p53单倍体缺失完全挽救了胚胎致死性，成年Brca1(delta11/delta11)p53+/-小鼠表现出癌症易感性和早衰。在这里，我们表明Chk2表达降低和/或缺失使Brca1(delta11/delta11)小鼠能够逃避胚胎致死性。与Brca1(delta11/delta11)p53+/-小鼠相比，Brca1(delta11/delta11)Chk2-/-小鼠的寿命显著延长。对Brca1(delta11/delta11)Chk2-/-小鼠的分析表明，由Brca1缺陷引起的p53依赖性凋亡和生长缺陷在快速增殖的器官中显著减弱。然而，在晚年，Brca1(delta11/delta11)Chk2-/-雌性小鼠发生了多种肿瘤。此外，ATM单倍体缺失也挽救了与Brca1缺陷相关的胚胎致死性和早衰。因此，响应Brca1缺陷，ATM-Chk2-p53信号通路的激活有助于抑制肿瘤转化，同时导致机体稳态受损。我们的数据突出了基因组完整性的精确维持对于抑制衰老和恶性肿瘤的关键作用，并提供了衰老与癌症之间的进一步联系。
