Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

Cristina Ribeiro-Silva, Mariangela Sabatella, Angela Helfricht, Jurgen A. Marteijn, Arjan F. Theil, Wim Vermeulen () and Hannes Lans ()
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Cristina Ribeiro-Silva: University Medical Center Rotterdam
Mariangela Sabatella: University Medical Center Rotterdam
Angela Helfricht: University Medical Center Rotterdam
Jurgen A. Marteijn: University Medical Center Rotterdam
Arjan F. Theil: University Medical Center Rotterdam
Wim Vermeulen: University Medical Center Rotterdam
Hannes Lans: University Medical Center Rotterdam

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract DNA damage sensors DDB2 and XPC initiate global genome nucleotide excision repair (NER) to protect DNA from mutagenesis caused by helix-distorting lesions. XPC recognizes helical distortions by binding to unpaired ssDNA opposite DNA lesions. DDB2 binds to UV-induced lesions directly and facilitates efficient recognition by XPC. We show that not only lesion-binding but also timely DDB2 dissociation is required for DNA damage handover to XPC and swift progression of the multistep repair reaction. DNA-binding-induced DDB2 ubiquitylation and ensuing degradation regulate its homeostasis to prevent excessive lesion (re)binding. Additionally, damage handover from DDB2 to XPC coincides with the arrival of the TFIIH complex, which further promotes DDB2 dissociation and formation of a stable XPC-TFIIH damage verification complex. Our results reveal a reciprocal coordination between DNA damage recognition and verification within NER and illustrate that timely repair factor dissociation is vital for correct spatiotemporal control of a multistep repair process.

Date: 2020
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DOI: 10.1038/s41467-020-18705-0

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