DNA damage, signalling and repair after exposure of cells to the sulphur mustard analogue 2-chloroethyl ethyl sulphide. 2009

Paul A Jowsey, and Faith M Williams, and Peter G Blain
Medical Toxicology Centre, Wolfson Unit, Newcastle University, Claremont Place, Newcastle upon Tyne NE2 4AA, United Kingdom. p.a.jowsey@ncl.ac.uk

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 (CEES) 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.

UI MeSH Term Description Entries
D009097 Multienzyme Complexes Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES. Complexes, Multienzyme
D009151 Mustard Gas Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). Dichlorodiethyl Sulfide,Sulfur Mustard,Bis(beta-chloroethyl) Sulfide,Di-2-chloroethyl Sulfide,Mustardgas,Psoriazin,Yellow Cross Liquid,Yperite,Di 2 chloroethyl Sulfide,Gas, Mustard,Mustard, Sulfur,Sulfide, Di-2-chloroethyl,Sulfide, Dichlorodiethyl
D010727 Phosphoric Diester Hydrolases A class of enzymes that catalyze the hydrolysis of one of the two ester bonds in a phosphodiester compound. EC 3.1.4. Phosphodiesterase,Phosphodiesterases,Hydrolases, Phosphoric Diester
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011755 Pyrophosphatases A group of enzymes within the class EC 3.6.1.- that catalyze the hydrolysis of diphosphate bonds, chiefly in nucleoside di- and triphosphates. They may liberate either a mono- or diphosphate. EC 3.6.1.-. Pyrophosphatase
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins

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