E2F-1 regulation by an unusual DNA damage-responsive DP subunit.

Nick Thangue (1) , Laura Ingram (1) , Shonagh Munro (1) , Amanda Coutts (1)

1 Clinical Pharmacology

E2F activity is negatively regulated by 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, down-regulates E2F activity. We report here 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, which co-incides 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, that acts independently of pRb and through a biochemically distinct mechanism, involved in negative regulation of E2F-1 activity.

Mots clés: Cell cycle; DNA damage; repression; DP-4; E2F-1

Nick Thangue, Laura Ingram, Shonagh Munro, Amanda Coutts. E2F-1 regulation by an unusual DNA damage-responsive DP subunit.. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.70⟩. ⟨hal-00547988⟩