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Lack of Poly(ADP-Ribose) Polymerase-1 Gene Product Enhances Cellular Sensitivity to Arsenite

¹ Genome Stability Laboratory, Department of Physiology; ² Oncology Research Institute; ³ Molecular and Cellular Immunology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; ⁴ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University; ⁵ Exploratory Research for Advanced Technology, Japan Science and Technology Corp., Osaka, Japan; and ⁶ Center for Radiological Research, Columbia University, New York, New York

Requests for reprints: M. Prakash Hande, Genome Stability Laboratory, Department of Physiology, Faculty of Medicine, National University of Singapore, Block MD9, 2 Medical Drive, Singapore 117597, Singapore. Phone: 65-6874-3664; Fax: 65-6778-8161; E-mail: phsmph{at}nus.edu.sg.

Arsenite (As³⁺) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for the treatment and prevention of arsenic exposure in human population. As poly(ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, role of PARP-1 was evaluated in arsenic-induced cytotoxic and genotoxic effects. Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1^–/– mouse embryonic fibroblasts (MEF; 40%) compared with PARP-1^+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite-induced DNA lesions in PARP-1^–/– MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite-treated PARP-1^–/– MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes majority of which have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Our results suggest an important role for PARP-1 gene product in the maintenance of chromosome-genome stability in response to arsenite-induced DNA damage.

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