TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
复制标题
DOI：
10.1038/nature21358
复制
发表时间：
2017-03-09
期刊：
影响因子：
64.8
通讯作者：
Chowdhury D
中科院分区：
文献类型：
--
作者：
Drané P;Brault ME;Cui G;Meghani K;Chaubey S;Detappe A;Parnandi N;He Y;Zheng XF;Botuyan MV;Kalousi A;Yewdell WT;Münch C;Harper JW;Chaudhuri J;Soutoglou E;Mer G;Chowdhury D
53BP1 是一种多功能双链断裂 (DSB) 修复蛋白，对于 B 淋巴细胞中的类别转换重组以及使 BRCA1 缺陷型肿瘤对 PARP 抑制剂敏感至关重要。所有 53BP1 活性的核心是通过串联 Tudor 结构域与组蛋白 H4 (H4K20me2) 的二甲基化赖氨酸 20 的相互作用招募到 DSB。在这里，我们鉴定了一种未表征的蛋白质，TIRR（Tudor 相互作用修复调节剂），它直接结合串联 Tudor 结构域并掩盖其 H4K20me2 结合基序。 DNA 损伤后，ATM 磷酸化 53BP1 并招募 RIF1 来解离 53BP1-TIRR 复合物。然而，TIRR 的过度表达会阻碍 53BP1 定位到 DSB，从而阻碍其功能。 TIRR 的耗尽会破坏核可溶部分中 53BP1 的稳定性，还会改变 DSB 诱导的以 53BP1 为中心的蛋白质复合物。这些发现将 TIRR 确定为一种影响 DSB 修复的新因素，利用一种独特的机制来掩盖 53BP1 的组蛋白甲基赖氨酸结合功能。
53BP1 is a multi-functional double-strand break (DSB) repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumors to PARP inhibitors. Central to all 53BP1 activities is its recruitment to DSBs via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, TIRR (Tudor Interacting Repair Regulator) that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1–TIRR complex. However, over-expression of TIRR impedes 53BP1 function by blocking its localization to DSBs. Depletion of TIRR destabilizes 53BP1 in the nuclear soluble fraction and also alters the DSB-induced protein complex centering 53BP1. These findings identify TIRR as a new factor that influences DSB repair utilizing a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.