SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells.
SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells.
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DOI：
10.1038/s41419-021-03437-w
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发表时间：
2021-02-08
影响因子：
9
通讯作者：
Kiltie AE
中科院分区：
文献类型：
--
作者：
Na J;Newman JA;Then CK;Syed J;Vendrell I;Torrecilla I;Ellermann S;Ramadan K;Fischer R;Kiltie AE
人MRE 11/RAD 50/NBS 1（MRN）复合物在感受和修复DNA DSB中起着至关重要的作用。MRE 11具有双重3′−5′核酸外切酶和核酸内切酶活性，并形成多功能MRN复合物的核心。我们先前鉴定了与翻译后MRE 11降解相关的MRE 11的C末端截短形式（TR-MRE 11）。在这里，我们确定了SPRTN作为形成TR-MRE 11的必需蛋白酶，并表征了这种MRE 11形式在其DNA损伤反应（DDR）中的作用。使用串联质谱和定点突变，SPRTN依赖性切割位点MRE 11之间的559和580个氨基酸的确定。尽管TR-MRE 11与其组成型核心复合物蛋白RAD 50和NBS 1的完整相互作用，但截短的MRE 11的两种核酸酶活性由于其与DNA的结合缺陷而显著降低。此外，MRE 11 C末端的缺乏降低了HR修复效率，这很可能是由于TR-MRE 11在DNA损伤位点的募集被取消，从而导致细胞放射敏感性增加。这种DNA修复缺陷型TR-MRE 11的存在可以解释我们之前的发现，即免疫组化检测的MRE 11蛋白高表达与膀胱癌患者根治性放疗后生存率的提高相关。
The human MRE11/RAD50/NBS1 (MRN) complex plays a crucial role in sensing and repairing DNA DSB. MRE11 possesses dual 3′−5′ exonuclease and endonuclease activity and forms the core of the multifunctional MRN complex. We previously identified a C-terminally truncated form of MRE11 (TR-MRE11) associated with post-translational MRE11 degradation. Here we identified SPRTN as the essential protease for the formation of TR-MRE11 and characterised the role of this MRE11 form in its DNA damage response (DDR). Using tandem mass spectrometry and site-directed mutagenesis, the SPRTN-dependent cleavage site for MRE11 was identified between 559 and 580 amino acids. Despite the intact interaction of TR-MRE11 with its constitutive core complex proteins RAD50 and NBS1, both nuclease activities of truncated MRE11 were dramatically reduced due to its deficient binding to DNA. Furthermore, lack of the MRE11 C-terminal decreased HR repair efficiency, very likely due to abolished recruitment of TR-MRE11 to the sites of DNA damage, which consequently led to increased cellular radiosensitivity. The presence of this DNA repair-defective TR-MRE11 could explain our previous finding that the high MRE11 protein expression by immunohistochemistry correlates with improved survival following radical radiotherapy in bladder cancer patients.
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影响因子：
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