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DNA damage, signalling and repair after exposure of cells to the sulphur mustard analogue 2-chloroethyl ethyl sulphide

Lookup NU author(s): Dr Paul Jowsey, Professor Faith Williams, Professor Peter Blain

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Abstract

Sulphur mustard (SM) is a blistering agent that is directly toxic to the skin and mucosal surfaces of the eye and respiratory system, Symptoms take several hours to develop and the mechanism of action is poorly understood although SM is able to alkylate nucleic acids and proteins. The ability of SM to form adducts with DNA has been documented, although there are limited data demonstrating how cells respond to this insult to repair the damage. This study used the sulphur mustard surrogate 2-chloroethyl ethyl sulphide (CFES) to identify DNA damage repair pathways and signalling events that are activated after exposure to the agent. A dose-dependent increase in DNA damage was observed in TK6 lymphoblastoid cells, which was associated with a loss of cell viability. Using both model human lymphoblastoid cell lines and pharmacological inhibitors, it was found that DNA damage induced by CEES was repaired by base excision repair(BER) and nucleotide excision repair (NER) pathways. Finally, CEES was found to induce the phosphorylation of p53 and Chk2 and these events were mediated by both the ATM ataxia telangiectasia mutated and ATR (ATM and Rad-3 related) protein kinases. (C) 2008 Elsevier Ireland Ltd. All rights reserved.


Publication metadata

Author(s): Jowsey PA, Williams FM, Blain PG

Publication type: Article

Publication status: Published

Journal: Toxicology

Year: 2009

Volume: 257

Issue: 3

Pages: 105-112

ISSN (print): 0300-483X

ISSN (electronic): 1879-3185

Publisher: Elsevier Ireland Ltd

URL: http://dx.doi.org/10.1016/j.tox.2008.12.001

DOI: 10.1016/j.tox.2008.12.001


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