Premium
Short dysfunctional telomeres impair the repair of arsenite‐induced oxidative damage in mouse cells
Author(s) -
Newman Jennifer P.A.,
Banerjee Birendranath,
Fang Wanru,
Poonepalli Anuradha,
Balakrishnan Lakshmidevi,
Low Grace Kah Mun,
Bhattacharjee Rabindra N.,
Akira Shizuo,
Jayapal Manikandan,
Melendez Alirio J.,
Baskar Rajamanickam,
Lee HanWoong,
Hande M. Prakash
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21276
Subject(s) - dna damage , telomere , genome instability , sodium arsenite , comet assay , biology , dna repair , telomerase , arsenite , oxidative stress , microbiology and biotechnology , programmed cell death , viability assay , shelterin , apoptosis , chemistry , genetics , dna , biochemistry , gene , arsenic , dna binding protein , organic chemistry , transcription factor
Telomeres and telomerase appear to participate in the repair of broken DNA ends produced by oxidative damage. Arsenite is an environmental contaminant and a potent human carcinogen, which induces oxidative stress on cells via the generation of reactive oxygen species affecting cell viability and chromosome stability. It promotes telomere attrition and reduces cell survival by apoptosis. In this study, we used mouse embryonic fibroblasts (MEFs) from mice lacking telomerase RNA component (mTERC −/− mice) with long (early passage or EP) and short (late passage or LP) telomeres to investigate the extent of oxidative damage by comparing the differences in DNA damage, chromosome instability, and cell survival at 24 and 48 h of exposure to sodium arsenite (As 3+ ; NaAsO 2 ). There was significantly high level of DNA damage in mTERC −/− cells with short telomeres as determined by alkaline comet assay. Consistent with elevated DNA damage, increased micronuclei (MN) induction reflecting gross genomic instability was also observed. Fluorescence in situ hybridization (FISH) analysis revealed that increasing doses of arsenite augmented the chromosome aberrations, which contributes to genomic instability leading to possibly apoptotic cell death and cell cycle arrest. Microarray analysis has revealed that As 3+ treatment altered the expression of 456 genes of which 20% of them have known functions in cell cycle and DNA damage signaling and response, cell growth, and/or maintenance. Results from our studies imply that short dysfunctional telomeres impair the repair of oxidative damage caused by arsenite. The results will have implications in risk estimation as well as cancer chemotherapy. J. Cell. Physiol. 214: 796–809, 2008. © 2007 Wiley‐Liss, Inc.