Damage sensor role of UV-DDB during base excision repair

Sunbok Jang, Namrata Kumar, Emily C. Beckwitt, Muwen Kong, Elise Fouquerel, Vesna Rapić-Otrin, Rajendra Prasad, Simon C. Watkins, Cindy Khuu, Chandrima Majumdar, Sheila S. David, Samuel H. Wilson, Marcel P. Bruchez, Patricia L. Opresko, Bennett Van Houten

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

UV-DDB, a key protein in human global nucleotide excision repair (NER), binds avidly to abasic sites and 8-oxo-guanine (8-oxoG), suggesting a noncanonical role in base excision repair (BER). We investigated whether UV-DDB can stimulate BER for these two common forms of DNA damage, 8-oxoG and abasic sites, which are repaired by 8-oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease (APE1), respectively. UV-DDB increased both OGG1 and APE1 strand cleavage and stimulated subsequent DNA polymerase β-gap filling activity by 30-fold. Single-molecule real-time imaging revealed that UV-DDB forms transient complexes with OGG1 or APE1, facilitating their dissociation from DNA. Furthermore, UV-DDB moves to sites of 8-oxoG repair in cells, and UV-DDB depletion sensitizes cells to oxidative DNA damage. We propose that UV-DDB is a general sensor of DNA damage in both NER and BER pathways, facilitating damage recognition in the context of chromatin.

Original languageEnglish
Pages (from-to)695-703
Number of pages9
JournalNature Structural and Molecular Biology
Volume26
Issue number8
DOIs
StatePublished - 1 Aug 2019

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