The radiomimetic enediyne C-1027 induces unusual DNA damage responses to double-strand breaks

Biochemistry
Daniel R Kennedy, Terry A Beerman

Abstract

Cells lacking the protein kinase ataxia telangiectasia mutated (ATM) have defective responses to DNA double-strand breaks (DSBs), including an inability to activate damage response proteins such as p53. However, we previously showed that cells lacking ATM robustly activate p53 in response to DNA strand breaks induced by the radiomimetic enediyne C-1027. To gain insight into the nature of C-1027-induced ATM-independent damage responses to DNA DSBs, we further examined the molecular mechanisms underlying the cellular response to this unique radiomimetic agent. Like ionizing radiation (IR) and other radiomimetics, breaks induced by C-1027 efficiently activate ATM by phosphorylation at Ser1981, yet unlike other radiomimetics and IR, DNA breaks induced by C-1027 result in normal phosphorylation of p53 and the cell cycle checkpoint kinases (Chk1 and Chk2) in the absence of ATM. In the presence of ATM, but under ATM and Rad3-related kinase (ATR) deficient conditions, C-1027 treatment resulted in a decrease in the level of Chk1 phosphorylation but not in the level of p53 and Chk2 phosphorylation. Only when cells were deficient in both ATM and ATR was there a reduction in the level of phosphorylation of each of these DNA damage response...Continue Reading

References

Jun 1, 1995·Bioorganic & Medicinal Chemistry·J M BattigelloB J Carter
May 24, 1996·Journal of Medicinal Chemistry·A L Smith, K C Nicolaou
Feb 7, 1998·Genes & Development·J D SilicianoM B Kastan
Jan 30, 1999·Genes & Development·R S TibbettsR T Abraham
Mar 29, 2000·Environmental and Molecular Mutagenesis·R R TiceY F Sasaki
May 10, 2000·Current Opinion in Cell Biology·K Collins
Apr 3, 2002·The Journal of Biological Chemistry·Jaroslaw Dziegielewski, Terry A Beerman
Jan 16, 2003·Cell·Anne M CasperThomas W Glover
Jan 31, 2003·Nature·Christopher J Bakkenist, Michael B Kastan
Feb 4, 2003·Nature Reviews. Cancer·Andrei V Gudkov, Elena A Komarova
Mar 4, 2003·Nature Reviews. Cancer·Yosef Shiloh
Sep 6, 2003·Current Biology : CB·Hiroyuki TakaiTitia de Lange
Oct 9, 2003·The EMBO Journal·Tamar UzielYosef Shiloh
Aug 18, 2004·Genes & Development·Paul R AndreassenToshiyasu Taniguchi
Jan 26, 2005·The Journal of Biological Chemistry·Jia Li, David F Stern

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Citations

Jul 4, 2009·Acta Pharmacologica Sinica·Yong-Zhan ZhenYong-Su Zhen
Jan 17, 2009·Cancer Research·Terry A BeermanMary M McHugh
Nov 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Daniel R KennedyTerry A Beerman
Jun 15, 2014·FEBS Letters·Zdenka Bartosova, Lumir Krejci
Sep 18, 2014·Asian Pacific Journal of Cancer Prevention : APJCP·Fei-Fei HanYong-Su Zhen
Apr 7, 2012·Biochemical and Biophysical Research Communications·Hong-Ying ZhenLi-Jun Ma
Feb 6, 2013·Cancer Biology & Therapy·Derek Woods, John J Turchi
Apr 30, 2015·The Journal of Pharmacy and Pharmacology·Christina C AndrosDaniel R Kennedy
Apr 9, 2014·Biochemical and Biophysical Research Communications·Hong-Ying ZhenYu-Lin Li

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