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 - Funding Information:
We thank G. Gibson and C. Wallace for help with troubleshooting related to imaging. We thank W. Vermeulen (Erasmus MC) for the generous gift of the mCherry-DDB2 vector. We greatly appreciate N. Kad, C. Kisker and J. Kuper for helpful discussions and comments on the manuscript. This work was supported by funding from the National Institutes of Health including R01ES019566, R01ES028686 (B.V.H.) and R33ES025606 (B.V.H. and P.L.O.), P30CA047904 (Hillman Cancer Center), R01EB017268 (M.P.B.), R01CA067985 (S.S.D.) and 1ZIAES050158 and 1ZIAES050159 (S.H.W.). E.C.B. was supported on a T32 training grant (T32GM088119). C.K. was supported by an NIEHS T32 training grant (ES007059).
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 -