A novel DDB2 mutation causes defective recognition of UV-induced DNA damages and prevalent equine squamous cell carcinoma

Autor: M. Singer-Berk, Yan Wang, Kaoru Sugasawa, Rebecca R. Bellone, Steven E. Artandi, James M. Ford, Lu Chen
Rok vydání: 2020
Předmět:
DNA Repair
Mutant
medicine.disease_cause
Biochemistry
law.invention
chemistry.chemical_compound
0302 clinical medicine
law
Squamous cell carcinoma
2.1 Biological and endogenous factors
Missense mutation
Aetiology
Cancer
0303 health sciences
Mutation
Xeroderma pigmentosum
Chromatin
DNA-Binding Proteins
Disease mutations
030220 oncology & carcinogenesis
Recombinant DNA
Carcinoma
Squamous Cell
Protein Binding
Ultraviolet Rays
Mutation
Missense
Biology
Eyelid Neoplasms
Article
03 medical and health sciences
DDB1
Rare Diseases
Equine genetics
Genetics
medicine
Animals
Climate-Related Exposures and Conditions
Horses
Molecular Biology
030304 developmental biology
Carcinoma
Cell Biology
DNA
UV-DDB
medicine.disease
Molecular biology
Chromatin association
Localized UV irradiation
Squamous Cell
chemistry
Nucleic Acid Conformation
Horse Diseases
Biochemistry and Cell Biology
Missense
Developmental Biology
Zdroj: DNA Repair (Amst)
ISSN: 1568-7856
Popis: Squamous cell carcinoma (SCC) occurs frequently in the human Xeroderma Pigmentosum (XP) syndrome and is characterized by deficient UV-damage repair. SCC is the most common equine ocular cancer and the only associated genetic risk factor is a UV-damage repair protein. Specifically, a missense mutation in horse DDB2 (T338M) was strongly associated with both limbal SCC and third eyelid SCC in three breeds of horses (Halflinger, Belgian, and Rocky Mountain Horses) and was hypothesized to impair binding to UV-damaged DNA. Here, we investigate DDB2-T338M mutant's capacity to recognize UV lesions in vitro and in vivo, together with human XP mutants DDB2-R273H and -K244E. We show that the recombinant DDB2-T338M assembles with DDB1, but fails to show any detectable binding to DNA substrates with or without UV lesions, due to a potential structural disruption of the rigid DNA recognition β-loop. Consistently, we demonstrate that the cellular DDB2-T338M is defective in its recruitment to focally radiated DNA damages, and in its access to chromatin. Thus, we provide direct functional evidence indicating the DDB2-T338M recapitulates molecular defects of human XP mutants, and is the causal loss-of-function allele that gives rise to equine ocular SCCs. Our findings shed new light on the mechanism of DNA recognition by UV-DDB and on the initiation of ocular malignancy.
Databáze: OpenAIRE
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