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

Lu Chen, Rebecca R. Bellone, Yan Wang, Moriel Singer-Berk, Kaoru Sugasawa, James M. Ford, Steven E. Artandi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number103022
JournalDNA Repair
Volume97
DOIs
StatePublished - Jan 2021

Keywords

  • Chromatin association
  • Disease mutations
  • Equine genetics
  • Localized UV irradiation
  • Squamous cell carcinoma
  • UV-DDB
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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