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

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

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)
240 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)25-41.e6
Number of pages23
JournalMolecular Cell
Issue number1
Early online date21 Jun 2018
Publication statusPublished - 5 Jul 2018


  • replication stress
  • histone methylation
  • replication fork replication
  • FANCD2
  • SETD1A
  • BOD1L
  • lysine methyltransferase


Dive into the research topics of 'Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2'. Together they form a unique fingerprint.

Cite this