Chk2 activates E2F-1 in response to DNA damage

Stevens, Craig; Smith, Linda; La Thangue, Nicholas B.

Abstract

The E2F-1 transcription factor is regulated during cell cycle progression and induced by cellular stress, such as DNA damage. We report that checkpoint kinase 2 (Chk2) regulates E2F-1 activity in response to the DNA-damaging agent etoposide. A Chk2 consensus phosphorylation site in E2F-1 is phosphorylated in response to DNA damage, resulting in protein stabilization, increased half-life, transcriptional activation and localization of phosphorylated E2F-1 to discrete nuclear structures. Expression of a dominant-negative Chk2 mutant blocks induction of E2F-1 and prevents E2F-1-dependent apoptosis. Moreover, E2F-1 is resistant to induction by etoposide in tumour cells expressing mutant chk2. Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. These results suggest a role for E2F-1 in checkpoint control and provide a plausible explanation for the tumour suppressor activity of E2F-1.

Citation

Stevens, C., Smith, L., & La Thangue, N. B. (2003). Chk2 activates E2F-1 in response to DNA damage. Nature Cell Biology, 5(5), 401-409. https://doi.org/10.1038/ncb974

• Journal Article Type: Article
• Acceptance Date: Mar 11, 2003
• Online Publication Date: Apr 22, 2003
• Publication Date: 2003-05
• Deposit Date: Apr 17, 2018
• Journal: Nature Cell Biology
• Print ISSN: 1465-7392
• Electronic ISSN: 1476-4679
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 5
• Pages: 401-409
• DOI: https://doi.org/10.1038/ncb974
• Keywords: Cell Biology
• Public URL: http://researchrepository.napier.ac.uk/Output/672010