E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit.
E2F activity is negatively regulated by retinoblastoma protein (pRb) through binding to the E2F-1 subunit. Within the E2F heterodimer, DP proteins are E2F partner subunits that allow proper cell cycle progression. In contrast to the other DP proteins, the newest member of the family, DP-4, downregulates E2F activity. In this study we report an unexpected role for DP-4 in regulating E2F-1 activity during the DNA damage response. Specifically, DP-4 is induced in DNA-damaged cells, upon which it binds to E2F-1 as a non-DNA-binding E2F-1/DP-4 complex. Consequently, depleting DP-4 in cells re-instates E2F-1 activity that coincides with increased levels of chromatin-bound E2F-1, E2F-1 target gene expression and associated apoptosis. Mutational analysis of DP-4 highlighted a C-terminal region, outside the DNA-binding domain, required for the negative control of E2F-1 activity. Our results define a new pathway, which acts independently of pRb and through a biochemically distinct mechanism, involved in negative regulation of E2F-1 activity.
Ingram
L
L
Laboratory of Cancer Biology, Department of Clinical Pharmacology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford, OX3 7DQ, UK.
Munro
S
S
Coutts
A S
AS
La Thangue
N B
NB
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D050680:Transcription Factor DP1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D021122:Protein Subunits; D034741:RNA, Small Interfering; C516920:TFDP3 protein, human; D050680:Transcription Factor DP1; D004247:DNA