UBE2O and USP7 co-regulate RECQL4 ubiquitinylation and homologous recombination-mediated DNA repair
UBE2O and USP7 co-regulate RECQL4 ubiquitinylation and homologous recombination-mediated DNA repair
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UBE2O 和 USP7 共同调节 RECQL4 泛素化和同源重组介导的 DNA 修复
DOI：
10.1096/fj.202100974rrr
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发表时间：
2022-01-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Xiaofei
中科院分区：
文献类型：
--
作者：
Huang, Qiuling;Qin, Dajiang;Zhang, Xiaofei
人类 RecQ DNA 解旋酶 RECQL4 通过调节 DNA 双链断裂 (DSB) 修复途径在维持基因组稳定性方面发挥着关键作用，因此参与衰老和癌症发病的调节。然而，RECQL4的调控机制，特别是其翻译后修饰，尚未得到充分阐明。在这里，我们报道了 E2/E3 混合泛素结合酶 UBE2O 与 RECQL4 发生物理相互作用，并介导 RECQL4 的多单泛素化，随后导致其蛋白酶体降解。在功能上，我们发现UBE2O抑制同源重组（HR）介导的DSB修复，这种抑制取决于其E2催化活性和RECQL4表达。从机制上讲，我们发现 UBE2O 减弱了 RECQL4 和 DNA 损伤修复蛋白、MRE11-RAD50-NBS1 复合物和 CtIP 的相互作用。此外，我们发现去泛素化酶 USP7 与 UBE2O 和 RECQL4 相互作用，并且拮抗 UBE2O 介导的 RECQL4 稳定性和功能的调节。总的来说，我们在 HR 介导的 DSB 修复过程中发现了泛素介导的 RECQL4 调节的新调节机制。
The human RecQ DNA helicase, RECQL4, plays a pivotal role in maintaining genomic stability by regulating the DNA double-strand breaks (DSBs) repair pathway, and is, thus, involved in the regulation of aging and cancer onset. However, the regulatory mechanisms of RECQL4, especially its post-translational modifications, have not been fully illustrated. Here, we report that the E2/E3 hybrid ubiquitin-conjugating enzyme, UBE2O, physically interacts with RECQL4, and mediates the multi-monoubiquitinylation of RECQL4, subsequently leading to its proteasomal degradation. Functionally, we showed that UBE2O inhibits homologous recombination (HR)-mediated DSBs repair, and this inhibition depends on its E2 catalytic activity and RECQL4 expression. Mechanistically, we showed that UBE2O attenuates the interaction of RECQL4 and DNA damage repair proteins, the MRE11-RAD50-NBS1 complex and CtIP. Furthermore, we show that deubiquitinylase USP7 interacts with both UBE2O and RECQL4, and in that it antagonizes UBE2O-mediated regulation of RECQL4 stability and function. Collectively, we found a novel regulatory mechanism of ubiquitin-mediated regulation of RECQL4 in HR-mediated DSBs repair process.