title: Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.
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.
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Xinghua
authors.initials: X
authors.lastname: Hou
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Neha
authors.initials: N
authors.lastname: Kabra
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ma
authors.forename: Shino
authors.initials: S
authors.lastname: Nemoto
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005047:Etoposide / Q000633:toxicity; D025461:Feedback, Physiological; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D034741:RNA, Small Interfering; D005047:Etoposide; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins