2. Academic Validation
  3. Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

  • Mol Cell. 2018 Jul 5;71(1):25-41.e6. doi: 10.1016/j.molcel.2018.05.018.
Martin R Higgs 1,  Koichi Sato 2,  John J Reynolds 3,  Shabana Begum 4,  Rachel Bayley 4,  Amalia Goula 4,  Audrey Vernet 3,  Karissa L Paquin 5,  David G Skalnik 6,  Wataru Kobayashi 2,  Minoru Takata 7,  Niall G Howlett 5,  Hitoshi Kurumizaka 2,  Hiroshi Kimura 8,  Grant S Stewart 9
Affiliations

Affiliations

  • 1 Lysine Methylation and DNA Damage Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].
  • 2 Department of Electrical Engineering and Bioscience, Waseda University, Shinjuku, Tokyo 169-8050, Japan.
  • 3 Genome Stability and Human Disease Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 4 Lysine Methylation and DNA Damage Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 5 Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
  • 6 Biology Department, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
  • 7 Laboratory of DNA Damage Signaling, Department of Late Effects Studies Radiation Biology Center, Kyoto University Yoshida konoe cho, Sakyo ku, Kyoto 606-8501, Japan.
  • 8 Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa Prefecture 226-8501, Japan.
  • 9 Genome Stability and Human Disease Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].
PMID: 29937342 DOI: 10.1016/j.molcel.2018.05.018
Abstract

Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

Keywords

BOD1L; FANCD2; SETD1A; histone methylation; lysine methyltransferase; replication fork replication; replication stress.

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