TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A

Alex Pines, Madelon Dijk, Matthew Makowski, Elisabeth M. Meulenbroek, Mischa G. Vrouwe, Yana van der Weegen, Marijke Baltissen, Pim J. French, Martin E. van Royen, Martijn S. Luijsterburg, Leon H. Mullenders, Michiel Vermeulen, Wim Vermeulen (), Navraj S. Pannu () and Haico van Attikum ()
Additional contact information
Alex Pines: Leiden University Medical Center
Madelon Dijk: Leiden University Medical Center
Matthew Makowski: Radboud University Nijmegen
Elisabeth M. Meulenbroek: Leiden University
Mischa G. Vrouwe: Leiden University Medical Center
Yana van der Weegen: Leiden University Medical Center
Marijke Baltissen: Radboud University Nijmegen
Pim J. French: Erasmus University Medical Center
Martin E. van Royen: Erasmus University Medical Center
Martijn S. Luijsterburg: Leiden University Medical Center
Leon H. Mullenders: Leiden University Medical Center
Michiel Vermeulen: Radboud University Nijmegen
Wim Vermeulen: Erasmus University Medical Center
Navraj S. Pannu: Leiden University
Haico van Attikum: Leiden University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA–DDB1–CUL4A–RBX1 cullin–RING ubiquitin ligase complex (CRLCSA). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin. TRiC’s binding to CSA ensures its stability and DDB1-dependent assembly into the CRLCSA complex. Consequently, loss of TRiC leads to mislocalization and depletion of CSA, as well as impaired transcription recovery following UV damage, suggesting defects in TC-NER. Furthermore, Cockayne syndrome (CS)-causing mutations in CSA lead to increased TRiC binding and a failure to compose the CRLCSA complex. Thus, we uncover CSA as a TRiC substrate and reveal that TRiC regulates CSA-dependent TC-NER and the development of CS.

Date: 2018
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DOI: 10.1038/s41467-018-03484-6

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