Journal
CELL DEATH AND DIFFERENTIATION
Volume 18, Issue 1, Pages 122-132Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.70
Keywords
cell cycle; E2F-1; DP-4; repression; DNA damage
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Funding
- MRC
- CRUK
- EU
- LRF
- AICR
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [G0500905, G1000807] Funding Source: researchfish
- MRC [G0500905, G1000807] Funding Source: UKRI
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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. Cell Death and Differentiation (2011) 18, 122-132; doi: 10.1038/cdd.2010.70; published online 18 June 2010
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