Crosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin.
Crosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin.
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DOI：
10.1038/s41467-022-32920-x
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发表时间：
2022-09-01
影响因子：
16.6
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中科院分区：
文献类型：
--
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DNA末端切除是通过各种类型的翻译后修饰来启动同源重组的微妙调控，但SUMOylation在这一过程中的参与尚不完全清楚。在这里，我们发现MRE11在切除受损的染色质时需要SUMOylation来保护它免受泛素介导的降解。在DSB诱导下，PIAS1促进染色质上的MRE11 summoylation，启动DNA末端切除。然后，MRE11主要在离开DSB位点后被SENP3去苏甲基化。SENP3缺乏导致MRE11降解失败并在染色质上积累，导致基因组不稳定。我们进一步表明，与癌症相关的SUMOylation受损的MRE11突变体表现出DNA修复能力受损。因此，我们证明MRE11 SUMOylation协同泛素化是由PIAS1和SENP3动态控制的，以促进DNA末端切除并维持基因组稳定性。DNA末端切除启动DNA同源重组修复需要精细调控。这项研究表明SUMOylation和泛素化之间的相互作用维持了染色质上MRE11的稳态，从而促进了基因组的稳定。
DNA end resection is delicately regulated through various types of post-translational modifications to initiate homologous recombination, but the involvement of SUMOylation in this process remains incompletely understood. Here, we show that MRE11 requires SUMOylation to shield it from ubiquitin-mediated degradation when resecting damaged chromatin. Upon DSB induction, PIAS1 promotes MRE11 SUMOylation on chromatin to initiate DNA end resection. Then, MRE11 is deSUMOylated by SENP3 mainly after it has moved away from DSB sites. SENP3 deficiency results in MRE11 degradation failure and accumulation on chromatin, causing genome instability. We further show that cancer-related MRE11 mutants with impaired SUMOylation exhibit compromised DNA repair ability. Thus, we demonstrate that MRE11 SUMOylation in coordination with ubiquitylation is dynamically controlled by PIAS1 and SENP3 to facilitate DNA end resection and maintain genome stability. DNA end resection initiating DNA repair by homologous recombination needs to be delicately regulated. This study shows the interplay between SUMOylation and ubiquitylation maintains MRE11 homeostasis on chromatin, thus facilitating genome stability.
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影响因子：
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Ceccaldi R;Rondinelli B;D'Andrea AD
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