RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and IPO11.
RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and IPO11.
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DOI：
10.1016/j.isci.2022.105115
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发表时间：
2022-10-21
期刊：
影响因子：
5.8
通讯作者：
Yang, Hongying
中科院分区：
文献类型：
--
作者：
Zhang, Yarui;Ou, Guomin;Ye, Zhujing;Zhou, Zhou;Cao, Qianlin;Li, Mengting;Wang, Jingdong;Cao, Jianping;Yang, Hongying
共济失调毛细血管扩张症突变蛋白激酶（ATM）是DNA损伤反应的核心蛋白，其转录后水平的调控机制尚不清楚。在这里，它被确定为蛋白Reprimo（RPRM）下调ATM蛋白水平，导致受损的DNA修复和增强细胞的放射敏感性。从机制上讲，尽管主要定位在细胞质中，但RPRM在X射线诱导后不久就移位到细胞核，与ATM相互作用并促进其核输出和蛋白酶体降解。RPRM核转位涉及其由细胞周期蛋白依赖性激酶4/6（CDK 4/6）介导的丝氨酸98处的磷酸化，并且需要Importin-11（IPO 11）。重要的是，IPO 11调节的辐照后的RRRM核输入对于其对ATM的调节至关重要。因此，RPRM过表达及其磷酸化抑制使细胞对遗传毒性剂如辐射敏感，而RPRM缺乏显著增加了体外和体内对辐射诱导的损伤的抗性。这些发现建立了一个重要的调节机制，其中ATM是负调制的RRRM。RRRM负调控ATM，从而决定细胞对DNA损伤的敏感性在核输入时，RRRM与ATM结合，促进ATM核输出和降解RRRM核输入由CDK 4/6介导的磷酸化状态控制，IPO 11对诱导的RRRM核转位至关重要分子生物学;细胞生物学
How the ataxia telangiectasia mutated (ATM) protein kinase, a core protein in DNA damage response, is regulated at post-transcription level remains unclear. Here it is identified that protein Reprimo (RPRM) downregulates ATM protein levels, resulting in impaired DNA repair and enhanced cellular radiosensitivity. Mechanistically, although primarily localized in the cytoplasm, RPRM translocates to the nucleus shortly after induced by X-irradiation, interacts with ATM and promotes its nuclear export and proteasomal degradation. The RPRM nuclear translocation involves its phosphorylation at serine 98 mediated by cyclin-dependent kinases 4/6 (CDK4/6), and requires Importin-11 (IPO11). Of importance, IPO11-regulated RPRM nuclear import upon irradiation is essential for its regulation on ATM. Thus, RPRM overexpression and its phosphorylation inhibition sensitize cells to genotoxic agents such as irradiation, whereas RPRM deficiency significantly increases resistance to radiation-induced damage both in vitro and in vivo. These findings establish a crucial regulatory mechanism in which ATM is negatively modulated by RPRM. RPRM negatively regulates ATM, thus determining cellular sensitivity to DNA damage On nuclear import, RPRM binds to ATM, promotes ATM nuclear export and degradation RPRM nuclear import is governed by its phosphorylation status mediated by CDK4/6 IPO11 is essential to the nuclear translocation of RPRM on induction Molecular biology; Cell biology
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影响因子：
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作者：
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作者：
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