The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms
The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms
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DOI：
10.1101/gad.321125.118
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发表时间：
2019-03-01
影响因子：
10.5
通讯作者：
Morris, Joanna R.
中科院分区：
文献类型：
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作者：
Garvin, Alexander J.;Walker, Alexandra K.;Morris, Joanna R.
DNA双链断裂（DSB）反应中的SUMOylation（小泛素样修饰物）调节修复因子的募集、活性和清除。然而，我们对deSUMOylation在这一过程中的作用的理解是有限的。本研究通过对deSUMOylase SENP2的研究，确定了deSUMOylase在同源重组（HR）和非同源末端连接（NHEJ）中的不同机制作用。我们发现MDC1的受调控的去氧氧化可防止过度的sumo化及其RNF4-VCP介导的dsb清除，从而促进NHEJ。相反，我们发现HR对SUMO可用性的敏感性不同，并且需要SENP2活动来提供SUMO。SENP2作为染色体3q扩增的一部分在许多癌症中被扩增。SENP2表达的增加延长了MDC1的焦点保留，增加了NHEJ和放射抗性。总的来说，我们的数据揭示了deSUMOylation差异启动细胞对DSB的反应，并证明了SENP2调节DSB修复反应的能力。
SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.