Journal Article

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

Baltissen, Marijke, Mullenders, Leon H., Vrouwe, Mischa G., Meulenbroek, Elisabeth M., Pines, Alex, Luijsterburg, Martijn S., Makowski, Matthew, van der Weegen, Yana, Pannu, Navraj S., Dijk, Madelon, van Royen, Martin E., van Attikum, Haico, Vermeulen, Wim, French, Pim J., Vermeulen, Michiel

2018

Overview

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 (CRL CSA ). Despite its vital role in TC-NER, little is known about the regulation of the CRL CSA 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 CRL CSA 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 CRL CSA complex. Thus, we uncover CSA as a TRiC substrate and reveal that TRiC regulates CSA-dependent TC-NER and the development of CS. An integrated network of chaperones and protein degradation machineries called the proteostasis network (PN) is required to maintain protein homeostasis. Here the authors show that one of the components of the PN, the chaperonin TRiC, interacts with the core transcription-coupled nucleotide excision repair protein CSA to ensure its assembly into the CRLCSA complex.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/44 / 13/51 / 13/89 / 14/35 / 14/63 / 38/77 / 45/70 / 631/337/1427/1430 / 631/45/470/1981 / 82/58 / 82/83 / Binding / Blotting, Western / Cell Line, Tumor / Cell Survival - genetics / Cell Survival - radiation effects / Chaperonin Containing TCP-1 - genetics / Chaperonin Containing TCP-1 - metabolism / Cockayne syndrome / Cockayne Syndrome - genetics / Crosslinking / Cullin / Deoxyribonucleic acid / DNA / DNA Damage - genetics / DNA Damage - radiation effects / DNA Repair Enzymes - genetics / DNA Repair Enzymes - metabolism / DNA-directed RNA polymerase / Humanities and Social Sciences / Humans / Immunoprecipitation / Lesions / Mass Spectrometry / Mass spectroscopy / Microscopy, Fluorescence / multidisciplinary / Mutation / Mutation - genetics / Nucleotide excision repair / Protein A / Ribonucleic acid / RNA / RNA Interference / RNA polymerase / RNA polymerase II / Science / Science (multidisciplinary) / Stalling / Substrates / Transcription / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription, Genetic - genetics / Transcription, Genetic - radiation effects / Ubiquitin / Ubiquitin-protein ligase / Ultraviolet Rays