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

Martin R Higgs, Koichi Sato, John J Reynolds, Shabana Begum, Rachel Bayley, Amalia Goula, Audrey Vernet, Karissa L Paquin, David G Skalnik, Wataru Kobayashi, Minoru Takata, Niall G Howlett, Hitoshi Kurumizaka, Hiroshi Kimura, Grant S Stewart

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)25-41.e6
Number of pages24
JournalMolecular Cell
Issue number1
Early online date21 Jun 2018
Publication statusPublished - 5 Jul 2018


  • A549 Cells
  • DNA/biosynthesis
  • DNA Replication/physiology
  • Epigenesis, Genetic/physiology
  • Fanconi Anemia Complementation Group D2 Protein/genetics
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase/genetics
  • Histones/genetics
  • Humans
  • Methylation
  • Molecular Chaperones/genetics
  • Nucleosomes/genetics
  • Rad51 Recombinase/genetics


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