Ye Qi, Ma Jian, Wang Zixi, Li Lei, Liu Tianjie, Wang Bin, Zhu Lizhe, Lei Yuzeshi, Xu Shan, Wang Ke, Jian Yanlin, Ma Bohan, Fan Yizeng, Liu Jing, Gao Yang, Huang Haojie, Li Lei
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nat Commun. 2024 Dec 5;15(1):10596. doi: 10.1038/s41467-024-54978-5.
53BP1 plays an important role in DNA double-strand break (DSB) repair and this activity is negatively regulated by its interaction with Tudor interacting repair regulator (TIRR). However, how the TIRR-53BP1 repair axis is regulated in response to DNA damage remains elusive. Here, we demonstrate that TIRR is translocated to the cytoplasm and degraded upon DNA damage. Ubiquitination of TIRR at lysine 187 by DTX3L is a critical process that regulates NHEJ pathway activity and PARP inhibitor sensitivity by facilitating XPO1-mediated TIRR nuclear export and degradation after DNA damage. We show that DTX3L is overexpressed in prostate cancers in patients and that decreased expression of TIRR due to DTX3L overexpression impairs the negative regulatory effect of TIRR on 53BP1, which consequently induces HR deficiency and chromosomal instability and sensitizes prostate cancer cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work reveals a dual action of DTX3L on TIRR degradation and nuclear exportation and identifies DTX3L as an upstream regulator of the TIRR-53BP1 axis that governs DNA repair pathway choice and PARP inhibitor sensitivity. These findings suggest that TIRR ubiquitination and DTX3L overexpression could be viable biomarkers predicting PARP inhibitor sensitivity in cancers.
53BP1在DNA双链断裂（DSB）修复中发挥重要作用，并且该活性通过其与都铎相互作用修复调节因子（TIRR）的相互作用而受到负调控。然而，TIRR-53BP1修复轴如何响应DNA损伤进行调节仍不清楚。在此，我们证明TIRR在DNA损伤时易位至细胞质并被降解。DTX3L介导的TIRR赖氨酸187位点的泛素化是一个关键过程，它通过促进DNA损伤后XPO1介导的TIRR核输出和降解来调节非同源末端连接（NHEJ）途径活性和PARP抑制剂敏感性。我们发现DTX3L在前列腺癌患者中过表达，并且由于DTX3L过表达导致的TIRR表达降低会损害TIRR对53BP1的负调控作用，从而导致同源重组（HR）缺陷和染色体不稳定，并使前列腺癌细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂敏感。我们的研究揭示了DTX3L对TIRR降解和核输出的双重作用，并确定DTX3L是TIRR-53BP1轴的上游调节因子，该轴控制DNA修复途径的选择和PARP抑制剂敏感性。这些发现表明，TIRR泛素化和DTX3L过表达可能是预测癌症中PARP抑制剂敏感性的可行生物标志物。
