Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage

The nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sir2 (silent information regulator 2) regulates gene silencing in yeast and promotes lifespan extension during caloric restriction. The mammalian homologue of Sir2 (SIRT1) regulates p53, NF-kappaB and Forkhead transcription factors, and is implicated in stress response. This report shows that the cell-cycle and Apoptosis regulator E2F1 induces SIRT1 expression at the transcriptional level. Furthermore, SIRT1 binds to E2F1 and inhibits E2F1 activities, forming a negative feedback loop. Knockdown of SIRT1 by small interference RNA (siRNA) increases E2F1 transcriptional and apoptotic functions. DNA damage by etoposide causes E2F1-dependent induction of SIRT1 expression and knockdown of SIRT1 increases sensitivity to etoposide. These results reveal a mutual regulation between E2F1 and SIRT1 that affects cellular sensitivity to DNA damage.