Title: Damage sensor role of UV-DDB during base excision repair.

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

Published In Nat Struct Mol Biol, (2019 Aug)

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.

PubMed ID: 31332353

MeSH Terms: Cell Line; DNA Damage; DNA Glycosylases/chemistry; DNA Glycosylases/metabolism; DNA Repair/physiology*; DNA-(Apurinic or Apyrimidinic Site) Lyase/chemistry; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/physiology*; Guanine/analogs & derivatives; Guanine/metabolism; Humans; Kinetics; Models, Molecular; Protein Binding; Protein Conformation; Protein Interaction Mapping; Pyrimidine Dimers/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Single Molecule Imaging; Substrate Specificity; Xeroderma Pigmentosum/pathology