Cancer-associated 53BP1 mutations induce DNA damage repair defects.
Cancer-associated 53BP1 mutations induce DNA damage repair defects.
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DOI：
10.1016/j.canlet.2020.12.033
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发表时间：
2020-12
期刊：
影响因子：
9.7
通讯作者：
Jiajia Zhang;Zhenzhen Yan;Yukun Wang;Yaguang Wang;Xin Guo;Ju Jing;Xiangnan Dong;Shasha Dong-Shasha-Don
中科院分区：
文献类型：
--
作者：
Jiajia Zhang;Zhenzhen Yan;Yukun Wang;Yaguang Wang;Xin Guo;Ju Jing;Xiangnan Dong;Shasha Dong-Shasha-Don
TP53结合蛋白1（53BP1）在DNA损伤修复和维持基因组稳定性中起重要作用。然而，53BP1在人类癌症中的突变尚未得到系统的研究。在这里，我们分析了来自癌症基因组图谱，国际癌症基因组联盟和癌症体细胞突变目录数据库的34种人类癌症中53BP1的541个体细胞突变。在这些与癌症相关的53BP1突变中，截短突变破坏了53BP1的核定位，从而取消了其在DNA损伤修复中的生物学功能。此外，通过生物化学分析和结构建模，我们研究了关键结构域的错义突变导致DNA损伤修复缺陷的详细分子机制。总之，我们的结果揭示了一组癌症相关的53BP1突变的功能缺陷。
TP53 binding protein 1 (53BP1) plays an important role in DNA damage repair and maintaining genomic stability. However, the mutations of 53BP1 in human cancers have not been systematically examined. Here, we have analyzed 541 somatic mutations of 53BP1 across 34 types of human cancer from databases of The Cancer Genome Atlas, International Cancer Genome Consortium and Catalogue of Somatic Mutations in Cancer. Among these cancer-associated 53BP1 mutations, truncation mutations disrupt the nuclear localization of 53BP1 thus abolish its biological functions in DNA damage repair. Moreover, with biochemical analyses and structural modeling, we have examined the detailed molecular mechanism by which missense mutations in the key domains causes the DNA damage repair defects. Taken together, our results reveal the functional defects of a set of cancer-associated 53BP1 mutations.