title: XRN2 Links Transcription Termination to DNA Damage and Replication Stress.
abstract: XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.
authors.affiliation: Department of Neurosurgery, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Julio C
authors.identifier: 0000-0002-0854-7866
authors.initials: JC
authors.lastname: Morales
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Richard
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Praveen L
authors.initials: PL
authors.lastname: Patidar
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Motea
authors.affiliation: Department of Neurosurgery, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Tuyen T
authors.initials: TT
authors.lastname: Dang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D004261:DNA Replication; D005095:Exoribonucleases / Q000235:genetics* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D023281:Genomics; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D064251:Multifunctional Enzymes; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D020365:RNA Helicases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D064251:Multifunctional Enzymes; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D005095:Exoribonucleases; C120903:XRN2 protein, human; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases