PARP inhibition during alkylation-induced genotoxic stress signals a cell cycle checkpoint response mediated by ATM |
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| Authors: | Michael J. Carrozza Donna F. Stefanick Julie K. Horton Padmini S. Kedar Samuel H. Wilson |
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| Affiliation: | 1. Universidade de São Paulo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Av. do Café, s/n, 14040-903, Brazil;2. Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, 14404-600, Brazil;3. Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada and;4. the National Institute of Biological Sciences, Beijing 102206, China;1. Division of Bariatric and Advanced Gastrointestinal Surgery, Department of Surgery. Stony Brook University Medical Center, Stony Brook, New York;2. Department of Preventative Medicine, Stony Brook University Medical Center, Stony Brook, New York;3. Department of Applied Mathematics and Statistics, Stony Brook University Medical Center. Stony Brook, New York;1. QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4029, Australia;2. The University of Queensland Centre for Clinical Research, Royal Brisbane and Women''s Hospital Campus, Herston, Queensland 4029, Australia;3. BrizBrain and Spine, The Wesley Hospital, Evan Thomson Building, Level 10, Auchenflower, Queensland 4066, Australia;1. Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People''s Republic of China;2. Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA |
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| Abstract: | By limiting cell cycle progression following detection of DNA damage, checkpoints are critical for cell survival and genome stability. Methylated DNA damage, when combined with inhibition of PARP activity, results in an ATR-dependent S phase delay of the cell cycle. Here, we demonstrate that another checkpoint kinase, ATM, also is involved in the DNA damage response following treatment with a sub-lethal concentration of MMS combined with the PARP inhibitor 4-AN. Both ATM and PARP activities are important for moderating cellular sensitivity to MMS. Loss of ATM activity, or that of its downstream effector Chk2, limited the duration of the S phase delay. The combination of MMS and 4-AN resulted in ATM and Chk2 phosphorylation and the time course of phosphorylation for both kinases correlated with the S phase delay. Chk2 phosphorylation was reduced in the absence of ATM activity. The Chk2 phosphorylation that remained in the absence of ATM appeared to be dependent on ATR and DNA-PK. The results demonstrate that, following initiation of base excision repair and inhibition of PARP activity, ATM activation is critical for preventing the cell from progressing through S phase, and for protection against MMS-induced cytotoxicity. |
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