Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 2H7, Canada.
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 2H7, Canada.
Cell Rep. 2018 Jan 9;22(2):383-395. doi: 10.1016/j.celrep.2017.12.047.
Ring1-YY1-binding protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. However, several PRC1 members were recently shown to function in DNA repair. Here, we report that RYBP preferentially binds K63-ubiquitin chains via its Npl4 zinc finger (NZF) domain. Since K63-linked ubiquitin chains are assembled at DNA double-strand breaks (DSBs), we examined the contribution of RYBP to DSB repair. Surprisingly, we find that RYBP is K48 polyubiquitylated by RNF8 and rapidly removed from chromatin upon DNA damage by the VCP/p97 segregase. High expression of RYBP competitively inhibits recruitment of BRCA1 repair complex to DSBs, reducing DNA end resection and homologous recombination (HR) repair. Moreover, breast cancer cell lines expressing high endogenous RYBP levels show increased sensitivity to DNA-damaging agents and poly ADP-ribose polymerase (PARP) inhibition. These data suggest that RYBP negatively regulates HR repair by competing for K63-ubiquitin chain binding.
Ring1-YY1 结合蛋白（RYBP）是非典型多梳抑制复合物 1（PRC1）的成员，与其他 PRC1 成员一样，它最常被描述为转录调节剂。然而，最近有研究表明，一些 PRC1 成员在 DNA 修复中发挥作用。在这里，我们报告 RYBP 通过其 Npl4 锌指（NZF）结构域优先结合 K63-泛素链。由于 K63 连接的泛素链在 DNA 双链断裂（DSB）处组装，我们研究了 RYBP 对 DSB 修复的贡献。令人惊讶的是，我们发现 RYBP 被 RNF8 进行 K48 多泛素化，并在 DNA 损伤时通过 VCP/p97 分选酶迅速从染色质中移除。RYBP 的高表达会竞争性抑制 BRCA1 修复复合物与 DSB 的结合，从而减少 DNA 末端切除和同源重组（HR）修复。此外，表达高水平内源性 RYBP 的乳腺癌细胞系对 DNA 损伤剂和聚 ADP-核糖聚合酶（PARP）抑制剂的敏感性增加。这些数据表明，RYBP 通过竞争 K63-泛素链结合来负调控 HR 修复。
