Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA.
Nat Commun. 2023 Mar 31;14(1):1810. doi: 10.1038/s41467-023-37499-5.
53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer.
53BP1 通过介导 DNA 末端切除失活来促进非同源末端连接（NHEJ）而非同源重组（HR）修复。泛素化在调节 53BP1 与 DNA 双链断裂（DSB）解离中起着重要作用。然而，这一过程是如何被调控的仍知之甚少。在这里，我们证明了 TRABID 去泛素化酶在体内水平与 53BP1 结合，并调节 53BP1 在 DSB 位点的保留。TRABID 去泛素化由 E3 泛素连接酶 SPOP 介导的 53BP1 的 K29 连接多泛素化，防止 53BP1 从 DSB 解离，从而导致 HR 缺陷和染色体不稳定性。过表达 TRABID 的前列腺癌细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂高度敏感。我们的工作表明，TRABID 通过诱导 53BP1 在 DSB 位点的持续保留，促进 NHEJ 修复而非 HR，从而在 DNA 修复过程中促进 NHEJ 修复而非 HR，提示 TRABID 过表达可能预测 HR 缺陷以及 PARP 抑制剂在前列腺癌中的潜在治疗用途。
