Nature Cell Biology
- 8, 1025 - 1031 (2006)
Published online: 6 August 2006; | doi:10.1038/ncb1468
Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damageChuangui Wang1, Lihong Chen1, Xinghua Hou1, Zhenyu Li1, Neha Kabra1, Yihong Ma1, Shino Nemoto2, Toren Finkel2, Wei Gu3, W. Douglas Cress1 & Jiandong Chen11
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. 2
Cardiovascular Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. 3
Institute of Cancer Genetics and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY10032, USA.
Correspondence should be addressed to Jiandong Chen jchen@moffitt.usf.edu 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- B 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.
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