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EMBO reports 8, 11, 1074–1079 (2007)
doi:10.1038/sj.embor.7401084
AOP Published online: 12 October 2007
Reactive oxygen-mediated damage to a human DNA replication and repair protein
Beatriz Montaner1*, Peter O'Donovan1*, Olivier Reelfs1, Conal M Perrett1, Xiaohong Zhang1, Yao-Zhong Xu3, Xiaolin Ren3, Peter Macpherson1, David Frith2 & Peter Karran1
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1 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK
2 Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
3 Department of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
To whom correspondence should be addressed
Peter Karran Tel: +44 20 7269 3870; Fax: +44 20 7269 3801; E-mail: peter.karran@cancer.org.uk
* These authors contributed equally to this work
Received 22 January 2007; Accepted 30 August 2007; Published online 12 October 2007.
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Abstract
Ultraviolet A (UVA) makes up more than 90% of incident terrestrial ultraviolet radiation. Unlike shorter wavelength UVB, which damages DNA directly, UVA is absorbed poorly by DNA and is therefore considered to be less hazardous. Organ transplant patients treated with the immunosuppressant azathioprine frequently develop skin cancer. Their DNA contains 6-thioguanine—a base analogue that generates DNA-damaging singlet oxygen (1O2) when exposed to UVA. Here, we show that this 1O2 damages proliferating cell nuclear antigen (PCNA), the homotrimeric DNA polymerase sliding clamp. It causes covalent oxidative crosslinking between the PCNA subunits through a histidine residue in the intersubunit domain. Crosslinking also occurs after treatment with higher—although still moderate—doses of UVA alone or with chemical oxidants. Chronic accumulation of oxidized proteins is linked to neurodegenerative disorders and ageing. Our findings identify oxidative damage to an important DNA replication and repair protein as a previously unrecognized hazard of acute oxidative stress.
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