The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics.
The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics.
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DOI：
10.1016/j.celrep.2019.08.106
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发表时间：
2019-10
期刊：
影响因子：
8.8
通讯作者：
K. Wagner;K. Kunz;Tanja Piller;G. Tascher;Soraya Hölper;Per Stehmeier;Jan Keiten-Schmitz;M. Schick;U. Keller;S. Müller
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文献类型：
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作者：
K. Wagner;K. Kunz;Tanja Piller;G. Tascher;Soraya Hölper;Per Stehmeier;Jan Keiten-Schmitz;M. Schick;U. Keller;S. Müller
泛素相关 SUMO 通路的信号传导依赖于协调的结合和解结合事件。 SUMO 特异性解偶联酶可以平衡 SUMO 化，但缺乏对其底物特异性和调节的全面了解。通过表征 SENP6，我们将 N 端多 SIM 域定义为将 SENP6 定位到 SUMO 链的关键决定因素。蛋白质组分析揭示了 SENP6 在染色质组织和 DNA 损伤反应 (DDR) 十字路口的功能网络。 SENP6 在端粒和着丝粒染色质结构域充当 SUMO 擦除器，并确定粘连蛋白复合物的 SUMO 化状态和染色质关联。重要的是，SENP6 是驱动 ATR-Chk1 激活的 hPSO4/PRP19 复合物的一部分。 SENP6 缺陷会损害 ATR 辅因子 ATRIP 的染色质关联，从而损害响应阿非迪霉素诱导的复制应激的 Chk1 信号传导的激活，并使细胞对 DNA 损伤敏感。我们提出 SENP6 通过平衡蛋白质复合物的染色质驻留来协调染色质动力学和基因组稳定性网络的一般作用。
Signaling by the ubiquitin-related SUMO pathway relies on coordinated conjugation and deconjugation events. SUMO-specific deconjugating enzymes counterbalance SUMOylation, but comprehensive insight into their substrate specificity and regulation is missing. By characterizing SENP6, we define an N-terminal multi-SIM domain as a critical determinant in targeting SENP6 to SUMO chains. Proteomic profiling reveals a network of SENP6 functions at the crossroads of chromatin organization and DNA damage response (DDR). SENP6 acts as a SUMO eraser at telomeric and centromeric chromatin domains and determines the SUMOylation status and chromatin association of the cohesin complex. Importantly, SENP6 is part of the hPSO4/PRP19 complex that drives ATR-Chk1 activation. SENP6 deficiency impairs chromatin association of the ATR cofactor ATRIP, thereby compromising the activation of Chk1 signaling in response to aphidicolin-induced replicative stress and sensitizing cells to DNA damage. We propose a general role of SENP6 in orchestrating chromatin dynamics and genome stability networks by balancing chromatin residency of protein complexes.