Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage

  • Nat Cell Biol. 2006 Sep;8(9):1025-31. doi: 10.1038/ncb1468.
Chuangui Wang  1 ,  Lihong Chen ,  Xinghua Hou ,  Zhenyu Li ,  Neha Kabra ,  Yihong Ma ,  Shino Nemoto ,  Toren Finkel ,  Wei Gu ,  W Douglas Cress ,  Jiandong Chen
Affiliations
  • 1. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
PMID: 16892051 DOI: 10.1038/ncb1468
Abstract

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.