Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor
Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor
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DOI：
10.1073/pnas.1403737111
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发表时间：
2014-08-05
影响因子：
11.1
通讯作者：
La Thangue, Nicholas B.
中科院分区：
文献类型：
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作者：
Carr, Simon M.;Munro, Shonagh;La Thangue, Nicholas B.
视网膜母细胞瘤肿瘤抑制蛋白pRb是细胞周期进程的关键调节剂和DNA损伤反应的介导剂。K810的赖氨酸甲基化发生在关键的Cdk磷酸化基序中，使pRb处于低磷酸化的生长抑制状态。我们在这里表明，甲基K810是由串联的都铎结构域包含肿瘤蛋白p53结合蛋白1（53BP1）。与甲基化K810 pRb肽复合的53BP1的结构解析强调了53BP1串联tudor结构域在识别甲基化赖氨酸和周围残基中的作用。值得注意的是，53BP1与甲基K810的结合发生在E2启动子结合因子靶基因上，并允许pRb活性与DNA损伤反应有效地整合。我们的研究结果拓宽了53BP1的细胞靶谱，并表明53BP1在调节pRb肿瘤抑制活性中的先前未鉴定的作用。
The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.