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Nat Struct Mol Biol. 2019 Aug;26(8):695-703. doi: 10.1038/s41594-019-0261-7. Epub 2019 Jul 22.

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

Author information

1
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
2
UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
3
Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
5
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
6
Molecular Biophysics and Structural Biology Graduate Program, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, PA, USA.
7
Department of Biochemistry and Molecular Biology, Thomas Jefferson University and Sydney Kimmel Medical College, Philadelphia, PA, USA.
8
Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
9
Genomic Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
10
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
11
Department of Chemistry, University of California, Davis, Davis, CA, USA.
12
Biochemistry, Molecular, Cellular and Developmental Graduate Group, University of California, Davis, Davis, CA, USA.
13
Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, USA.
14
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
15
Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA.
16
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. vanhoutenb@upmc.edu.
17
UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. vanhoutenb@upmc.edu.
18
Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. vanhoutenb@upmc.edu.
19
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. vanhoutenb@upmc.edu.

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.

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