10779/crick.12732839.v1
Melisa Guven
Melisa
Guven
Reto Brem
Reto
Brem
Peter Macpherson
Peter
Macpherson
Matthew Peacock
Matthew
Peacock
Peter Karran
Peter
Karran
Oxidative damage to RPA limits the nucleotide excision repair capacity of human cells
The Francis Crick Institute
2020
Cells, Cultured
DNA Damage
DNA Repair
DNA-Binding Proteins
Enzyme-Linked Immunosorbent Assay
Humans
Immunoblotting
Oxidation-Reduction
Oxidative Stress
Photosensitivity Disorders
Photosensitizing Agents
Replication Protein A
Skin Neoplasms
Thioguanine
Ultraviolet Rays
Karran
CS-ack
1103 Clinical Sciences
1112 Oncology and Carcinogenesis
Dermatology & Venereal Diseases
2020-07-29 13:21:46
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Oxidative_damage_to_RPA_limits_the_nucleotide_excision_repair_capacity_of_human_cells/12732839
Nucleotide excision repair (NER) protects against sunlight-induced skin cancer. Defective NER is associated with photosensitivity and a high skin cancer incidence. Some clinical treatments that cause photosensitivity can also increase skin cancer risk. Among these, the immunosuppressant azathioprine and the fluoroquinolone antibiotics ciprofloxacin and ofloxacin interact with UVA radiation to generate reactive oxygen species that diminish NER capacity by causing protein damage. The replication protein A (RPA) DNA-binding protein has a pivotal role in DNA metabolism and is an essential component of NER. The relationship between protein oxidation and NER inhibition was investigated in cultured human cells expressing different levels of RPA. We show here that RPA is limiting for NER and that oxidative damage to RPA compromises NER capability. Our findings reveal that cellular RPA is surprisingly vulnerable to oxidation, and we identify oxidized forms of RPA that are associated with impaired NER. The vulnerability of NER to inhibition by oxidation provides a connection between cutaneous photosensitivity, protein damage, and increased skin cancer risk. Our findings emphasize that damage to DNA repair proteins, as well as to DNA itself, is likely to be an important contributor to skin cancer risk.