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首页> 美国卫生研究院文献>PLoS Genetics >Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair
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Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair

机译：Alternative-NHEJ是哺乳动物染色体断裂修复的机械途径。

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Characterizing the functional overlap and mutagenic potential of different pathways of chromosomal double-strand break (DSB) repair is important to understand how mutations arise during cancer development and treatment. To this end, we have compared the role of individual factors in three different pathways of mammalian DSB repair: alternative-nonhomologous end joining (alt-NHEJ), single-strand annealing (SSA), and homology directed repair (HDR/GC). Considering early steps of repair, we found that the DSB end-processing factors KU and CtIP affect all three pathways similarly, in that repair is suppressed by KU and promoted by CtIP. In contrast, both KU and CtIP appear dispensable for the absolute level of total-NHEJ between two tandem I-SceI–induced DSBs. During later steps of repair, we find that while the annealing and processing factors RAD52 and ERCC1 are important to promote SSA, both HDR/GC and alt-NHEJ are significantly less dependent upon these factors. As well, while disruption of RAD51 causes a decrease in HDR/GC and an increase in SSA, inhibition of this factor did not affect alt-NHEJ. These results suggest that the regulation of DSB end-processing via KU/CtIP is a common step during alt-NHEJ, SSA, and HDR/GC. However, at later steps of repair, alt-NHEJ is a mechanistically distinct pathway of DSB repair, and thus may play a unique role in mutagenesis during cancer development and therapy.
机译：表征染色体双链断裂（DSB）修复不同途径的功能重叠和诱变潜力，对于了解突变在癌症发展和治疗过程中如何产生是非常重要的。为此，我们比较了个体因素在哺乳动物DSB修复的三种不同途径中的作用：交替非同源末端连接（alt-NHEJ），单链退火（SSA）和同源性定向修复（HDR / GC）。考虑到修复的早期步骤，我们发现DSB最终加工因子KU和CtIP同样影响所有这三个途径，因为KU抑制了修复并且CtIP促进了修复。相反，KU和CtIP似乎对于两个串联I-SceI诱导的DSB之间的总NHEJ绝对水平是必不可少的。在随后的维修步骤中，我们发现虽然退火和加工因子RAD52和ERCC1对于促进SSA很重要，但HDR / GC和alt-NHEJ都对这些因子的依赖性明显降低。同样，虽然RAD51的破坏导致HDR / GC降低和SSA升高，但抑制该因子并没有影响alt-NHEJ。这些结果表明，在alt-NHEJ，SSA和HDR / GC中，通过KU / CtIP调节DSB最终处理是一个常见步骤。然而，在修复的后续步骤中，alt-NHEJ是DSB修复机制上截然不同的途径，因此可能在癌症发展和治疗过程中的诱变中发挥独特作用。

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