Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining
Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining
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微阵列筛选揭示了通过非同源末端连接与 DNA 修复相关的非传统 SUMO 结合模式
DOI：
10.1101/2021.01.20.427433
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Cabello-Lobato M
中科院分区：
文献类型：
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作者：
Cabello-Lobato M
SUMOylation对于包括DNA双链断裂（DSBs）修复在内的大量细胞信号通路至关重要。如果修复不当，dsb会导致癌症、神经退行性变、免疫缺陷和早衰。基于系统的蛋白质组微阵列筛选，结合广泛应用的碳足迹和高分辨率结构分析，我们在非同源末端连接（NHEJ）修复DSB的DNA修复蛋白XRCC4上定义了两个非常规的sumo2结合模块。从机制上讲，SUMO2与XRCC4的相互作用与XRCC4与至少两种其他NHEJ蛋白- XLF和DNA连接酶4 （LIG4）的结合不相容。这些发现与在缺乏这些因素或其功能障碍的情况下，XRCC4的SUMO2相互作用在NHEJ的不同阶段作为备用途径是一致的。这些场景不仅与致癌有关，也与精确抗癌药物的设计和基于CRISPR/ cas9的基因编辑的优化有关。这项工作揭示了拓扑特异性SUMO识别及其通过NHEJ调节DSB修复的潜力。此外，它还提供了丰富的二元SUMO受体资源，可用于揭示广泛细胞过程中的调控层。
SUMOylation is critical for a plethora of cellular signalling pathways including the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Based on systematic proteome microarray screening combined with widely applicable carbene footprinting and high-resolution structural profiling, we define two non-conventional SUMO2-binding modules on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, interaction of SUMO2 with XRCC4 is incompatible with XRCC4 binding to at least two other NHEJ proteins – XLF and DNA ligase 4 (LIG4). These findings are consistent with SUMO2 interactions of XRCC4 acting as backup pathways at different stages of NHEJ, in the absence of these factors or their dysfunctioning. Such scenarios are not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. This work reveals insights into topology-specific SUMO recognition and its potential for modulating DSB repair by NHEJ. Moreover, it provides a rich resource on binary SUMO receptors that can be exploited for uncovering regulatory layers in a wide array of cellular processes.