Epigenetic Regulation of DNA Repair Pathway Choice by MacroH2A1 Splice Variants Ensures Genome Stability
Epigenetic Regulation of DNA Repair Pathway Choice by MacroH2A1 Splice Variants Ensures Genome Stability
复制标题
DOI：
10.1016/j.molcel.2020.06.028
复制
发表时间：
2020-09-03
期刊：
影响因子：
16
通讯作者：
Oberdoerffer, Philipp
中科院分区：
文献类型：
--
作者：
Sebastian, Robin;Hosogane, Eri K.;Oberdoerffer, Philipp
失活的X染色体(Xi)对基因组的异常具有先天易感性。复制应激(RS)已被认为是一个潜在的原因，但保护XI不稳定的机制仍不清楚。在这里，我们证明了宏H_2A1.2，一种富含在XI上的RS保护性组蛋白变体，对于Xi的完整性和雌性生存是必需的。从机械上讲，宏H_2A1.2中和了其结构不同、同样富含硅的选择性剪接变异体宏H_2A1.1。比较蛋白质组学确定了宏H2A1.1在交替末端连接(ALT-EJ)中的作用，这解释了在缺乏宏H2A1.2的情况下XI后期缺陷。通过同时耗尽大分子H_2A1.1或ALT-EJ因子来挽救基因组的不稳定性，而同时缺乏这两个大分子H_2A1变异体的小鼠没有明显的雌性缺陷。值得注意的是，在肿瘤细胞中，宏H_2A1剪接变异体不平衡也会影响ALT-EJ能力。综上所述，这些发现确定宏H2A1剪接是基因组维持的调节器，确保XI的完整性，并可能从更广泛的角度预测恶性细胞的DNA修复结果。
The inactive X chromosome (Xi) is inherently susceptible to genomic aberrations. Replication stress (RS) has been proposed as an underlying cause, but the mechanisms that protect from Xi instability remain unknown. Here, we show that macroH2A1.2, an RS-protective histone variant enriched on the Xi, is required for Xi integrity and female survival. Mechanistically, macroH2A1.2 counteracts its structurally distinct and equally Xi-enriched alternative splice variant, macroH2A1.1. Comparative proteomics identified a role for macroH2A1.1 in alternative end joining (alt-EJ), which accounts for Xi anaphase defects in the absence of macroH2A1.2. Genomic instability was rescued by simultaneous depletion of macroH2A1.1 or alt-EJ factors, and mice deficient for both macroH2A1 variants harbor no overt female defects. Notably, macroH2A1 splice variant imbalance affected alt-EJ capacity also in tumor cells. Together, these findings identify macroH2A1 splicing as a modulator of genome maintenance that ensures Xi integrity and may, more broadly, predict DNA repair outcome in malignant cells.