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Nucleic Acids Res. 2019 Nov 13. pii: gkz977. doi: 10.1093/nar/gkz977. [Epub ahead of print]

Transcription-coupled nucleotide excision repair is coordinated by ubiquitin and SUMO in response to ultraviolet irradiation.

Author information

1
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, the Netherlands.
2
Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden 2333 ZC, the Netherlands.
3
Department of Pathology, Cancer Treatment Screening Facility (CTSF), Erasmus Optical Imaging Centre (OIC), Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
4
Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Japan.
5
Department of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Abstract

Cockayne Syndrome (CS) is a severe neurodegenerative and premature aging autosomal-recessive disease, caused by inherited defects in the CSA and CSB genes, leading to defects in transcription-coupled nucleotide excision repair (TC-NER) and consequently hypersensitivity to ultraviolet (UV) irradiation. TC-NER is initiated by lesion-stalled RNA polymerase II, which stabilizes the interaction with the SNF2/SWI2 ATPase CSB to facilitate recruitment of the CSA E3 Cullin ubiquitin ligase complex. However, the precise biochemical connections between CSA and CSB are unknown. The small ubiquitin-like modifier SUMO is important in the DNA damage response. We found that CSB, among an extensive set of other target proteins, is the most dynamically SUMOylated substrate in response to UV irradiation. Inhibiting SUMOylation reduced the accumulation of CSB at local sites of UV irradiation and reduced recovery of RNA synthesis. Interestingly, CSA is required for the efficient clearance of SUMOylated CSB. However, subsequent proteomic analysis of CSA-dependent ubiquitinated substrates revealed that CSA does not ubiquitinate CSB in a UV-dependent manner. Surprisingly, we found that CSA is required for the ubiquitination of the largest subunit of RNA polymerase II, RPB1. Combined, our results indicate that the CSA, CSB, RNA polymerase II triad is coordinated by ubiquitin and SUMO in response to UV irradiation. Furthermore, our work provides a resource of SUMO targets regulated in response to UV or ionizing radiation.

PMID:
31722399
DOI:
10.1093/nar/gkz977

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