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Reactive oxygen‐mediated damage to a human DNA replication and repair protein
Author(s) -
Montaner Beatriz,
O'Donovan Peter,
Reelfs Olivier,
Perrett Conal M,
Zhang Xiaohong,
Xu YaoZhong,
Ren Xiaolin,
Macpherson Peter,
Frith David,
Karran Peter
Publication year - 2007
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7401084
Subject(s) - proliferating cell nuclear antigen , dna damage , dna glycosylase , oxidative stress , dna , dna repair , reactive oxygen species , dna replication , nucleotide excision repair , chemistry , oxidative phosphorylation , biology , biochemistry , microbiology and biotechnology
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 ( 1 O 2 ) when exposed to UVA. Here, we show that this 1 O 2 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.