Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2

Research output: Contribution to journalArticle

Authors

  • Koichi Sato
  • Amalia Goula
  • Audrey Vernet
  • Karissa Paquin
  • David Skalnik
  • Waturu Kobayashi
  • Minoru Takata
  • Niall Howlett
  • Hitoshi Kurumizaka
  • Hiroshi Kimura

Colleges, School and Institutes

External organisations

  • Department of Electrical Engineering and Bioscience, Waseda University, Shinjuku, Tokyo 169-8050, Japan
  • Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA
  • Biology Department, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
  • Laboratory of DNA Damage Signaling, Dept of Late Effects Studies Radiation Biology Center, Kyoto University Yoshida konoe cho, Sakyo ku, Kyoto 606-8501, Japan
  • Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa Pref. 226-8501, Japan

Abstract

Components of the Fanconi anaemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, thus 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 sensitises 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 via its ability to catalyse 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.

Details

Original languageEnglish
Pages (from-to)25-41
JournalMolecular Cell
Volume71
Issue number1
Early online date21 Jun 2018
Publication statusPublished - 5 Jul 2018