E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases

EMBO J. 2009 Oct 21;28(20):3185-95. doi: 10.1038/emboj.2009.258. Epub 2009 Sep 17.

Abstract

E2F1 is a key positive regulator of human cell proliferation and its activity is altered in essentially all human cancers. Deregulation of E2F1 leads to oncogenic DNA damage and anti-oncogenic apoptosis. The molecular mechanisms by which E2F1 mediates these two processes are poorly understood but are important for understanding cancer progression. During the G1-to-S phase transition, E2F1 associates through a short DHQY sequence with the cell-cycle regulator HCF-1 together with the mixed-lineage leukaemia (MLL) family of histone H3 lysine 4 (H3K4) methyltransferases. We show here that the DHQY HCF-1-binding sequence permits E2F1 to stimulate both DNA damage and apoptosis, and that HCF-1 and the MLL family of H3K4 methyltransferases have important functions in these processes. Thus, HCF-1 has a broader role in E2F1 function than appreciated earlier. Indeed, sequence changes in the E2F1 HCF-1-binding site can modulate both up and down the ability of E2F1 to induce apoptosis indicating that HCF-1 association with E2F1 is a regulator of E2F1-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Binding Sites
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA Damage / genetics
  • DNA Damage / physiology*
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • E2F1 Transcription Factor / physiology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histone-Lysine N-Methyltransferase / physiology
  • Host Cell Factor C1 / chemistry
  • Host Cell Factor C1 / genetics
  • Host Cell Factor C1 / metabolism*
  • Host Cell Factor C1 / physiology
  • Humans
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid

Substances

  • E2F1 Transcription Factor
  • E2F1 protein, human
  • HCFC1 protein, human
  • Host Cell Factor C1
  • Intracellular Signaling Peptides and Proteins
  • WDR5 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase