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摘要 : “DNA 聚合酶 ζ”(由REV3、REV7和一个相关因子REV1组成)介导涉及“跨损伤合成” (translesion synthesis)的一种类型的DNA 修复,因此其活性具有高度诱变性。

 “DNA 聚合酶 ζ”(由REV3、REV7和一个相关因子REV1组成)介导涉及“跨损伤合成” (translesion synthesis)的一种类型的DNA 修复,因此其活性具有高度诱变性。探索DNA损伤反应的两项研究聚焦作为一个因子的REV7 (亦称为MAD2L2),该因子本身能促进基因组完整性的维持。防止端粒末端被作为双链断裂(DSBs)识别出来、同时防止触发一个不合适的DNA损伤反应的几个保护性机制以前已经知道。现在,Jacqueline Jacobs及同事发现,REV7/MAD2L2通过抑制5′ 端的切除来抑制发生在去保护的端粒上和发生在由辐照诱导的DSBs上的依赖于同源性的修复。Sven Rottenberg及同事通过研究对PARP抑制剂的抵抗力的形成也得出了一个类似结论。他们发现,REV7/MAD2L2在缺少BRCA的细胞中和在免疫球蛋白类别转换过程中决定通道选择。


MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection


Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing1, 2. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3′ telomeric overhangs, indicating that MAD2L2 inhibits 5′ end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP3. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5′ end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis4. Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5′ end resection downstream of RIF1.

来源: Nature 浏览次数:0


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