DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity

• Published in: Nature communications 2024-12, Vol.15 (1), p.10596-15
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/19; 631/337/1427/2566; 631/80/2023/2022; 64/60; 82/58; 82/80; Active Transport, Cell Nucleus; Adenosine diphosphate; Animals; Biomarkers; Cell Line, Tumor; Cell Nucleus - metabolism; Chromosomal Instability; Cytoplasm; Damage; Degradation; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA Repair; Double-strand break repair; Exportin 1 Protein; Gene expression; Genomic instability; HEK293 Cells; Humanities and Social Sciences; Humans; Inhibitors; Karyopherins - metabolism; Lysine; Male; Mice; Molecular modelling; multidisciplinary; Non-homologous end joining; Nuclear transport; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Prostate; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteolysis - drug effects; Ribose; Science; Science (multidisciplinary); Sensitivity; Tumor Suppressor p53-Binding Protein 1 - genetics; Tumor Suppressor p53-Binding Protein 1 - metabolism; Ubiquitination; Yeast
• ISSN: 2041-1723
• 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. Several molecular mechanisms, including TIRR-53BP1 repair axis, regulate DNA repair pathway choice and PARP inhibitor sensitivity. Here, the authors show that ubiquitination of TIRR by DTX3L is a critical process that regulates NHEJ pathway activity and PARP inhibitor sensitivity by facilitating XPO1-mediated TIRR nuclear export and degradation upon DNA damage.