Short dysfunctional telomeres impair the repair of arsenite-induced oxidative damage in mouse cells.
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 (As3+; NaAsO2). 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 As3+ 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.
Newman
Jennifer P A
JP
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Banerjee
Birendranath
B
Fang
Wanru
W
Poonepalli
Anuradha
A
Balakrishnan
Lakshmidevi
L
Low
Grace Kah Mun
GK
Bhattacharjee
Rabindra N
RN
Akira
Shizuo
S
Jayapal
Manikandan
M
Melendez
Alirio J
AJ
Baskar
Rajamanickam
R
Lee
Han-Woong
HW
Hande
M Prakash
MP
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000187:drug effects; D033481:Chromosomes, Mammalian / Q000378:metabolism; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D020869:Gene Expression Profiling; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D046228:Microarray Analysis; D048629:Micronuclei, Chromosome-Defective; D018384:Oxidative Stress / Q000187:drug effects*; D012313:RNA / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000473:pathology*
D018053:Arsenites; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; C015001:arsenite