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.
Wang
Chuangui
C
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Chen
Lihong
L
Hou
Xinghua
X
Li
Zhenyu
Z
Kabra
Neha
N
Ma
Yihong
Y
Nemoto
Shino
S
Finkel
Toren
T
Gu
Wei
W
Cress
W Douglas
WD
Chen
Jiandong
J
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*
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