Hematology Center of Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou 215123, China.
Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, The First Affiliated Hospital, Soochow University School of Medicine, Suzhou 215123, China.
Sci Rep. 2017 Mar 27;7:45385. doi: 10.1038/srep45385.
Beclin 1 is a well-established core mammalian autophagy protein that is embryonically indispensable and has been presumed to suppress oncogenesis via an autophagy-mediated mechanism. Here, we show that Beclin 1 is a prenatal primary cytoplasmic protein but rapidly relocated into the nucleus during postnatal development in mice. Surprisingly, deletion of beclin1 in in vitro human cells did not block an autophagy response, but attenuated the expression of several DNA double-strand break (DSB) repair proteins and formation of repair complexes, and reduced an ability to repair DNA in the cells exposed to ionizing radiation (IR). Overexpressing Beclin 1 improved the repair of IR-induced DSB, but did not restore an autophagy response in cells lacking autophagy gene Atg7, suggesting that Beclin 1 may regulate DSB repair independent of autophagy in the cells exposed to IR. Indeed, we found that Beclin 1 could directly interact with DNA topoisomerase IIβ and was recruited to the DSB sites by the interaction. These findings reveal a novel function of Beclin 1 in regulation of DNA damage repair independent of its role in autophagy particularly when the cells are under radiation insult.
Beclin 1 是一种成熟的哺乳动物自噬核心蛋白，在胚胎发育中不可或缺，并且被认为通过自噬介导的机制抑制肿瘤发生。在这里，我们表明 Beclin 1 是一种产前主要细胞质蛋白，但在小鼠出生后的发育过程中迅速转移到细胞核中。令人惊讶的是，体外人类细胞中 beclin1 的缺失并没有阻断自噬反应，但削弱了几种 DNA 双链断裂 (DSB) 修复蛋白的表达和修复复合物的形成，并降低了暴露于电离辐射 (IR) 的细胞修复 DNA 的能力。过表达 Beclin 1 可改善 IR 诱导的 DSB 的修复，但不能恢复缺乏自噬基因 Atg7 的细胞中的自噬反应，表明 Beclin 1 可能在暴露于 IR 的细胞中独立于自噬调节 DSB 修复。事实上，我们发现 Beclin 1 可以直接与 DNA 拓扑异构酶 IIβ 相互作用，并通过相互作用被募集到 DSB 位点。这些发现揭示了 Beclin 1 在调节 DNA 损伤修复方面的新功能，独立于其在自噬中的作用，特别是当细胞受到辐射损伤时。
