TY - JOUR
T1 - Damage sensor role of UV-DDB during base excision repair
AU - Jang, Sunbok
AU - Kumar, Namrata
AU - Beckwitt, Emily C.
AU - Kong, Muwen
AU - Fouquerel, Elise
AU - Rapić-Otrin, Vesna
AU - Prasad, Rajendra
AU - Watkins, Simon C.
AU - Khuu, Cindy
AU - Majumdar, Chandrima
AU - David, Sheila S.
AU - Wilson, Samuel H.
AU - Bruchez, Marcel P.
AU - Opresko, Patricia L.
AU - Van Houten, Bennett
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071070717&partnerID=8YFLogxK
U2 - 10.1038/s41594-019-0261-7
DO - 10.1038/s41594-019-0261-7
M3 - Article
C2 - 31332353
AN - SCOPUS:85071070717
SN - 1545-9993
VL - 26
SP - 695
EP - 703
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 8
ER -