Laboratory of Respiratory Biology, National Institute of Environmental Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 2012 Oct 1;72(19):5080-90. doi: 10.1158/0008-5472.CAN-12-1484. Epub 2012 Aug 15.
The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80(-/-)) mice. RAP80(-/-) mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEF) derived from RAP80(-/-) mice underwent premature senescence compared with wild-type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80(-/-) thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80(-/-) mice were more susceptible to spontaneous lymphoma development and the development of 7,12-dimethylbenz(a)anthracene-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53(-/-) and p53(+/-) mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function.
含泛素相互作用基序的蛋白 RAP80 最近被发现通过促进几种 DDR 介质（包括 BRCA1）向电离辐射（IR）诱导的焦点的易位，在 DNA 损伤反应（DDR）信号中发挥关键作用。在这项研究中，我们研究了 RAP80 缺失对 RAP80 缺失（RAP80(-/-)）小鼠基因组稳定性和癌症发展易感性的影响。RAP80(-/-) 小鼠具有活力，并且没有表现出任何明显的发育缺陷。与野生型（WT）MEF 相比，源自 RAP80(-/-) 小鼠的小鼠胚胎成纤维细胞（MEF）经历过早衰老，对 IR 更敏感，并表现出更高水平的自发和 IR 诱导的基因组不稳定性。RAP80(-/-) 胸腺细胞对 IR 诱导的细胞死亡比 WT 胸腺细胞更敏感。RAP80(-/-) 小鼠对自发性淋巴瘤发展和 7,12-二甲基苯并（a）蒽诱导的乳腺肿瘤发展更敏感。此外，RAP80 的缺失加速了 p53(-/-) 和 p53(+/-) 小鼠中肿瘤的形成。我们的数据表明，RAP80 缺失促进基因组不稳定性，并增加癌症风险，这与 RAP80 表现出肿瘤抑制功能的概念一致。
