H2AX facilitates classical non-homologous end joining at the expense of limited nucleotide loss at repair junctions.
H2AX facilitates classical non-homologous end joining at the expense of limited nucleotide loss at repair junctions.
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H2AX 促进经典的非同源末端连接，但代价是修复连接处的核苷酸损失有限
DOI：
10.1093/nar/gkx715
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发表时间：
2017-10-13
影响因子：
14.9
通讯作者：
Xie AY
中科院分区：
文献类型：
--
作者：
Feng YL;Xiang JF;Liu SC;Guo T;Yan GF;Feng Y;Kong N;Li HD;Huang Y;Lin H;Cai XJ;Xie AY
磷酸化组蛋白H2 AX（γ H2 AX）是哺乳动物细胞中对DNA双链断裂（DSB）的染色质反应的重要调控因子。H2 AX缺陷增加了未修复的DSB和易位的数量，这部分与非同源末端连接（NHEJ）缺陷相关，并导致癌症中的基因组不稳定性。然而，γ H2 AX在一般DSB的NHEJ中的作用尚未明确。在这里，我们表明，尽管对总体NHEJ效率的影响很小，但H2 AX缺陷导致了对准确NHEJ和NHEJ产物中较短缺失的令人惊讶的偏倚。通过分析CRISPR/Cas9诱导的NHEJ并通过使用诱变NHEJ的新报告基因，我们发现γ H2 AX，沿着其相互作用蛋白MDC 1，是有效的经典NHEJ（C-NHEJ）所需的，但具有短的缺失和插入。上位性分析表明，共济失调毛细血管扩张突变（ATM）和染色质重塑复合物Tip 60/TRRAP/P400是必不可少的H2 AX功能。总之，这些数据表明，DSB的一个子集可能需要γ H2 AX介导的短距离核小体在断裂周围重新定位，以促进C-NHEJ，同时在NHEJ连接处损失一些额外的核苷酸。这可以防止诸如非修复和易位的结果，这些结果通常比来自局部NHEJ的短缺失和插入对基因组更不稳定。
Phosphorylated histone H2AX, termed ‘γH2AX’, mediates the chromatin response to DNA double strand breaks (DSBs) in mammalian cells. H2AX deficiency increases the numbers of unrepaired DSBs and translocations, which are partly associated with defects in non-homologous end joining (NHEJ) and contributing to genomic instability in cancer. However, the role of γH2AX in NHEJ of general DSBs has yet to be clearly defined. Here, we showed that despite little effect on overall NHEJ efficiency, H2AX deficiency causes a surprising bias towards accurate NHEJ and shorter deletions in NHEJ products. By analyzing CRISPR/Cas9-induced NHEJ and by using a new reporter for mutagenic NHEJ, we found that γH2AX, along with its interacting protein MDC1, is required for efficient classical NHEJ (C-NHEJ) but with short deletions and insertions. Epistasis analysis revealed that ataxia telangiectasia mutated (ATM) and the chromatin remodeling complex Tip60/TRRAP/P400 are essential for this H2AX function. Taken together, these data suggest that a subset of DSBs may require γH2AX-mediated short-range nucleosome repositioning around the breaks to facilitate C-NHEJ with loss of a few extra nucleotides at NHEJ junctions. This may prevent outcomes such as non-repair and translocations, which are generally more destabilizing to genomes than short deletions and insertions from local NHEJ.
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影响因子：
64.5
作者：
Alt FW;Zhang Y;Meng FL;Guo C;Schwer B
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作者：
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