2. Academic Validation
  3. CARM1 regulates replication fork speed and stress response by stimulating PARP1

CARM1 regulates replication fork speed and stress response by stimulating PARP1

  • Mol Cell. 2021 Feb 18;81(4):784-800.e8. doi: 10.1016/j.molcel.2020.12.010.
Marie-Michelle Genois 1,  Jean-Philippe Gagné 2,  Takaaki Yasuhara 1,  Jessica Jackson 3,  Sneha Saxena 1,  Marie-France Langelier 4,  Ivan Ahel 5,  Mark T Bedford 6,  John M Pascal 4,  Alessandro Vindigni 3,  Guy G Poirier 2,  Lee Zou 7
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
  • 2 Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City, QC G1V 0A6, Canada; CHU de Québec Research Center, CHUL Pavilion, Oncology Axis, Québec City, Québec G1V 4G2, Canada.
  • 3 Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
  • 5 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • 6 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
  • 7 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: zou.lee@mgh.harvard.edu.
PMID: 33412112 DOI: 10.1016/j.molcel.2020.12.010
Abstract

DNA replication forks use multiple mechanisms to deal with replication stress, but how the choice of mechanisms is made is still poorly understood. Here, we show that CARM1 associates with replication forks and reduces fork speed independently of its methyltransferase activity. The speeding of replication forks in CARM1-deficient cells requires RECQ1, which resolves reversed forks, and RAD18, which promotes translesion synthesis. Loss of CARM1 reduces fork reversal and increases single-stranded DNA (ssDNA) gaps but allows cells to tolerate higher replication stress. Mechanistically, CARM1 interacts with PARP1 and promotes PARylation at replication forks. In vitro, CARM1 stimulates PARP1 activity by enhancing its DNA binding and acts jointly with HPF1 to activate PARP1. Thus, by stimulating PARP1, CARM1 slows replication forks and promotes the use of fork reversal in the stress response, revealing that CARM1 and PARP1 function as a regulatory module at forks to control fork speed and the choice of stress response mechanisms.

Keywords

CARM1; PARP1; PARylation; PrimPol; RECQ1; fork reversal; fork speed; replication fork; replication stress; translesion synthesis.

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