Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Cancer Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Mol Cell. 2021 Jun 17;81(12):2583-2595.e6. doi: 10.1016/j.molcel.2021.03.039. Epub 2021 May 6.
53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.
53BP1 通过两种独立的机制影响基因组稳定性：（1）调节 DNA 双链断裂（DSB）修复，（2）增强 p53 活性。我们发现了一种与 53BP1 Tudor 结构域结合并阻止其招募到 DSB 的蛋白，即 Tudor 相互作用修复调节剂（TIRR）。在这里，我们阐明了 TIRR 如何在其招募到 DSB 之外影响 53BP1 的功能，并在生化上连接了 53BP1 的两个不同作用。TIRR 的缺失导致 p53 的基因转录激活功能异常增加，影响了几个 p53 介导的细胞命运程序。TIRR 抑制了 53BP1 的 Tudor 结构域与处于转录激活其靶基因准备状态的 p53（K382me2）的二甲基化形式之间的复合物形成。TIRR mRNA 表达水平与乳腺癌和前列腺癌中关键 p53 靶基因的表达呈负相关。此外，TIRR 的缺失在 p53 功能正常的肿瘤中选择性地不能耐受。因此，我们确定 TIRR 是 53BP1-p53 复合物的重要抑制剂。
