E2F3 is a mediator of DNA damage-induced apoptosis.
The E2F transcription factors have emerged as critical apoptotic effectors. Herein we report that the E2F family member E2F3a can be induced by DNA damage through transcriptional and posttranslational mechanisms. We demonstrate that the posttranslational induction of human E2F3a is dependent on the checkpoint kinases. Moreover, we show that human E2F3a is a substrate for the checkpoint kinases (chk kinases) and that mutation of the chk phosphorylation site eliminates the DNA damage inducibility of the protein. Furthermore, we demonstrate that E2F1 and E2F2 are transcriptionally induced by DNA damage in an E2f3-dependent manner. Finally, using both in vitro and in vivo approaches, we establish that E2f3 is required for DNA damage-induced apoptosis. Thus, our data reveal the novel ability of E2f3 to function as a master regulator of the DNA damage response.
Martinez
Luis A
LA
Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. lmartinez@biochem.umsmed.edu
Goluszko
Elzbieta
E
Chen
Hui-Zi
HZ
Leone
Gustavo
G
Post
Sean
S
Lozano
Guillermina
G
Chen
Zhenping
Z
Chauchereau
Anne
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000819:agonists / Q000378:metabolism*; D050704:E2F4 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050700:E2F5 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D014916:Whole-Body Irradiation; D009353:Zinostatin / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D034741:RNA, Small Interfering; D005047:Etoposide; D004317:Doxorubicin; D009353:Zinostatin; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1