E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases.
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.
Tyagi
Shweta
S
Center for Integrative Genomics, University of Lausanne, Génopode, Lausanne, Switzerland.
Herr
Winship
W
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051863:Host Cell Factor C1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D047908:Intracellular Signaling Peptides and Proteins; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase