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

Qi Ye, Jian Ma (), Zixi Wang, Lei Li, Tianjie Liu, Bin Wang, Lizhe Zhu, Yuzeshi Lei, Shan Xu, Ke Wang, Yanlin Jian, Bohan Ma, Yizeng Fan, Jing Liu, Yang Gao, Haojie Huang () and Lei Li ()
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Qi Ye: The First Affiliated Hospital of Xi’an Jiaotong University
Jian Ma: The First Affiliated Hospital of Xi’an Jiaotong University
Zixi Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Lei Li: The First Affiliated Hospital of Xi’an Jiaotong University
Tianjie Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Bin Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Lizhe Zhu: The First Affiliated Hospital of Xi’an Jiaotong University
Yuzeshi Lei: The First Affiliated Hospital of Xi’an Jiaotong University
Shan Xu: The First Affiliated Hospital of Xi’an Jiaotong University
Ke Wang: The First Affiliated Hospital of Xi’an Jiaotong University
Yanlin Jian: The First Affiliated Hospital of Xi’an Jiaotong University
Bohan Ma: The First Affiliated Hospital of Xi’an Jiaotong University
Yizeng Fan: The First Affiliated Hospital of Xi’an Jiaotong University
Jing Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Yang Gao: The First Affiliated Hospital of Xi’an Jiaotong University
Haojie Huang: Zhejiang University School of Medicine
Lei Li: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54978-5

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