Rad6-Bre1-mediated H2B ubiquitination regulates telomere replication by promoting telomere-end resection
Rad6-Bre1-mediated H2B ubiquitination regulates telomere replication by promoting telomere-end resection
复制标题
Rad6-Bre1介导的H2B泛素化通过促进端粒末端切除来调节端粒复制
DOI：
10.1093/nar/gkx101
复制
发表时间：
2017
影响因子：
14.9
通讯作者：
Jin-Qiu Zhou
中科院分区：
文献类型：
--
作者：
Zhenfang Wu;Jun Liu;Qiong-Di Zhang;De-Kang Lv;Nian-Feng Wu;Jin-Qiu Zhou
Rad6 和 Bre1 分别是泛素结合 E2 和 E3 酶，负责酿酒酵母中的组蛋白 H2B 赖氨酸 123 单泛素化 (H2Bub1)。先前的研究表明，Rad6 和 Bre1 调节端粒长度和重组。然而，潜在的分子机制仍然很大程度上未知。在此我们报告，H2BK123 突变导致端粒缩短，而 Ubp8 和/或 Ubp10（H2Bub1 的去泛素化酶）失活则以 Rad6-Bre1 依赖性方式导致端粒延长。在端粒酶缺陷的细胞中，Rad6-Bre1通路的失活会延缓端粒缩短率和衰老的开始，而UBP8和/或UBP10的缺失会加速衰老。因此，Rad6-Bre1 通路通过其在 H2Bub1 中的作用来调节端粒长度和重组。此外，Rad6–Bre1–H2Bub1 和 Mre11–Rad50–Xrs2 (MRX) 通路的失活会导致端粒酶缺陷细胞中的合成生长缺陷和端粒缩短，并显着加速衰老并消除端粒酶缺陷细胞中的 II 型端粒重组。此外，RAD6 或 BRE1 缺失或 H2BK123R 突变会减少端粒末端 ssDNA 的积累。这些结果支持Rad6-Bre1-H2Bub1与MRX协同促进端粒末端切除，从而正向调节端粒酶和重组依赖性端粒复制的模型。这项研究提供了组蛋白 H2B 泛素化和端粒复制之间的机制联系。
Rad6 and Bre1, ubiquitin-conjugating E2 and E3 enzymes respectively, are responsible for histone H2B lysine 123 mono-ubiquitination (H2Bub1) in Saccharomyces cerevisiae. Previous studies have shown that Rad6 and Bre1 regulate telomere length and recombination. However, the underlying molecular mechanism remains largely unknown. Herewe report that H2BK123 mutation results in telomere shortening, while inactivation of Ubp8 and/or Ubp10, deubiquitinases of H2Bub1, leads to telomere lengthening in Rad6–Bre1-dependent manner. In telomerasedeficient cells, inactivation of Rad6–Bre1 pathway retards telomere shortening rate and the onset of senescence, while deletion of UBP8 and/or UBP10 accelerates senescence. Thus, Rad6–Bre1 pathway regulates both telomere length and recombination through its role in H2Bub1. Additionally, inactivation of both Rad6–Bre1–H2Bub1 and Mre11–Rad50– Xrs2 (MRX) pathways causes synthetic growth defects and telomere shortening in telomeraseproficient cells, and significantly accelerates senescence and eliminates type II telomere recombination in telomerase-deficient cells. Furthermore, RAD6 or BRE1 deletion, or H2BK123Rmutation decreases the accumulation of ssDNA at telomere ends. These results support the model that Rad6–Bre1–H2Bub1 cooperates with MRX to promote telomere-end resection and thus positively regulates both telomeraseand recombination-dependent telomere replication. This study provides a mechanistic link between histone H2B ubiquitination and telomere replication.