title: Reactive oxygen-mediated damage to a human DNA replication and repair protein.
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 ((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.
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Montaner
authors.forename: Peter
authors.initials: P
authors.lastname: O'Donovan
authors.forename: Olivier
authors.initials: O
authors.lastname: Reelfs
authors.forename: Conal M
authors.initials: CM
authors.lastname: Perrett
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Xu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Ren
authors.forename: Peter
authors.initials: P
authors.lastname: Macpherson
authors.forename: David
authors.initials: D
authors.lastname: Frith
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016415:Sequence Alignment; D026082:Singlet Oxygen / Q000378:metabolism*; D013873:Thionucleotides / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D006150:Guanine Nucleotides; D016877:Oxidants; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D013873:Thionucleotides; C003964:6-thioguanylic acid; D026082:Singlet Oxygen