DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1

Wen-Ling Lin; Jung-Kuei Chen; Xuemei Wen; Wei He; Geovanny A Zarceno; Yutian Chen; Shi Chen; Tanya T Paull; Hung-Wen Liu

doi:10.1016/j.celrep.2022.111089

DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1

Cell Rep. 2022 Jul 19;40(3):111089. doi: 10.1016/j.celrep.2022.111089.

Authors

Wen-Ling Lin¹, Jung-Kuei Chen¹, Xuemei Wen², Wei He³, Geovanny A Zarceno⁴, Yutian Chen⁴, Shi Chen⁵, Tanya T Paull², Hung-Wen Liu⁶

Affiliations

¹ Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
² Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
³ Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA; School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
⁴ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
⁵ School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518055, China.
⁶ Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA; Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: h.w.liu@mail.utexas.edu.

PMID: 35858569
DOI: 10.1016/j.celrep.2022.111089

Abstract

R loops occur frequently in genomes and contribute to fundamental biological processes at multiple levels. Consequently, understanding the molecular and cellular biology of R loops has become an emerging area of research. Here, it is shown that poly(ADP-ribose) polymerase-1 (PARP-1) can mediate the association of DDX18, a putative RNA helicase, with R loops thereby modulating R-loop homeostasis in endogenous R-loop-prone and DNA lesion regions. DDX18 depletion results in aberrant endogenous R-loop accumulation, which leads to DNA-replication defects. In addition, DDX18 depletion renders cells more sensitive to DNA-damaging agents and reduces RPA32 and RAD51 foci formation in response to irradiation. Notably, DDX18 depletion leads to γH2AX accumulation and genome instability, and RNase H1 overexpression rescues all the DNA-repair defects caused by DDX18 depletion. Taken together, these studies uncover a function of DDX18 in R-loop-mediated events and suggest a role for PARP-1 in mediating the binding of specific DDX-family proteins with R loops in cells.

Keywords: CP: Molecular biology; DDX18; DNA damage; PARP-1; R loops; genome integrity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA
DNA Damage
DNA Repair
Genomic Instability
Humans
Poly(ADP-ribose) Polymerase Inhibitors*
R-Loop Structures*

Substances

Poly(ADP-ribose) Polymerase Inhibitors
DNA