Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins

Namrata Kumar, Arjan F. Theil, Vera Roginskaya, Yasmin Ali, Michael Calderon, Simon C. Watkins, Ryan P. Barnes, Patricia L. Opresko, Alex Pines, Hannes Lans, Wim Vermeulen and Bennett Houten ()
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Namrata Kumar: University of Pittsburgh School of Medicine
Arjan F. Theil: University Medical Center Rotterdam, Dr. Molewaterplein 40
Vera Roginskaya: UPMC Hillman Cancer Center
Yasmin Ali: University of Pittsburgh School of Medicine
Michael Calderon: University of Pittsburgh
Simon C. Watkins: University of Pittsburgh
Ryan P. Barnes: UPMC Hillman Cancer Center
Patricia L. Opresko: UPMC Hillman Cancer Center
Alex Pines: University Medical Center Rotterdam, Dr. Molewaterplein 40
Hannes Lans: University Medical Center Rotterdam, Dr. Molewaterplein 40
Wim Vermeulen: University Medical Center Rotterdam, Dr. Molewaterplein 40
Bennett Houten: University of Pittsburgh School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role of UV-DDB in stimulating base excision repair (BER) which raised several questions about the timing of UV-DDB arrival at 8-oxoguanine (8-oxoG), and the dependency of UV-DDB on the recruitment of downstream BER and NER proteins. Using two different approaches to introduce 8-oxoG in cells, we show that DDB2 is recruited to 8-oxoG immediately after damage and colocalizes with 8-oxoG glycosylase (OGG1) at sites of repair. 8-oxoG removal and OGG1 recruitment is significantly reduced in the absence of DDB2. NER proteins, XPA and XPC, also accumulate at 8-oxoG. While XPC recruitment is dependent on DDB2, XPA recruitment is DDB2-independent and transcription-coupled. Finally, DDB2 accumulation at 8-oxoG induces local chromatin unfolding. We propose that DDB2-mediated chromatin decompaction facilitates the recruitment of downstream BER proteins to 8-oxoG lesions.

Date: 2022
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DOI: 10.1038/s41467-022-28642-9

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