Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

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  • Andrea Björkman, Karolinska University Hospital og Karolinska Institute
  • ,
  • Søren L Johansen, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, , Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark., Department of Radiation Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark and Niels Bohr Institute, University of Copenhagen, Copenhagen DK-2100, Denmark., Hospital Lillebaelt, Middelfart, Denmark, University of Southern Denmark, Odense, Denmark, and Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Lin Lin
  • Mike Schertzer, PSL Research University
  • ,
  • Dimitris C Kanellis, Karolinska University Hospital og Karolinska Institute
  • ,
  • Anna-Maria Katsori, Karolinska University Hospital og Karolinska Institute
  • ,
  • Søren T Christensen, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark., Department of Radiation Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark and Niels Bohr Institute, University of Copenhagen, Copenhagen DK-2100, Denmark.
  • ,
  • Yonglun Luo
  • Jens S Andersen, Department of Biochemistry and Molecular Biology, Univ Southern Denmark, University of Southern Denmark, Department of Chemistry, Odense University, DK-5230 Odense M
  • ,
  • Simon J Elsässer, Karolinska University Hospital og Karolinska Institute
  • ,
  • Arturo Londono-Vallejo, PSL Research University
  • ,
  • Jiri Bartek, Karolinska University Hospital og Karolinska Institute
  • ,
  • Kenneth B Schou, Division of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome Scale Biology Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland, Division of Biochemistry, Department of Medical Biochemistry and Biophysics , Biochemistry & Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden., Karolinska University Hospital og Karolinska Institute, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 171 77 Solna, Sweden., Novartis Sweden AB, Stockholm, Sweden.

RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Polδ subunit Poldip3 form a complex and are/function mutually dependent in chromatin binding after replication stress. Loss of RTEL1 and Poldip3 leads to marked R-loop accumulation that is confined to sites of active replication, enhances endogenous replication stress, and fuels ensuing genomic instability. The impact of depleting RTEL1 and Poldip3 is epistatic, consistent with our proposed concept of these two proteins operating in a shared pathway involved in DNA replication control under stress conditions. Overall, our data highlight a previously unsuspected role of RTEL1 and Poldip3 in R-loop suppression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.

OriginalsprogEngelsk
TidsskriftGenes & Development
Vol/bind34
Nummer15-16
Sider (fra-til)1065-1074
Antal sider10
ISSN0890-9369
DOI
StatusUdgivet - 2020

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