TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A
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.
|Persistent URL||dx.doi.org/10.1038/s41467-018-03484-6, hdl.handle.net/1765/105448|
Pines, A. (Alex), Dijk, M. (Madelon), Makowski, M. (Matthew), Meulenbroek, E.M. (Elisabeth M.), Vrouwe, M.G, Van Der Weegen, Y. (Yana), … van Attikum, H. (2018). TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A. Nature Communications, 9(1). doi:10.1038/s41467-018-03484-6