A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response

Cell. 2018 Feb 22;172(5):1007-1021.e17. doi: 10.1016/j.cell.2018.01.032.

Abstract

MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers.

Keywords: DNA damage response; SETD1A; cyclin K; histone methyltransferase; leukemia; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocatalysis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cyclins / genetics
  • Cyclins / metabolism*
  • DNA Damage*
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism
  • Gene Expression Regulation, Leukemic
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Protein Binding
  • Protein Domains
  • Protein Stability
  • Transcription, Genetic

Substances

  • CCNK protein, human
  • Cyclins
  • Fanconi Anemia Complementation Group D2 Protein
  • Histones
  • histone H3 trimethyl Lys4
  • Histone-Lysine N-Methyltransferase
  • Setd1A protein, human