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Nat Commun. 2018 Mar 12;9(1):1040. doi: 10.1038/s41467-018-03484-6.

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

Author information

1
Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden, 2333 ZC, The Netherlands.
2
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
3
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
4
Department of Biophysical Structural Chemistry, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
5
Department of Neurology, Cancer Treatment Screening Facility (CTSF), Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
6
Department of Pathology, Cancer Treatment Screening Facility (CTSF), Erasmus Optical Imaging Centre (OIC), Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
7
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands. w.vermeulen@erasmusmc.nl.
8
Department of Biophysical Structural Chemistry, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. raj@chem.leidenuniv.nl.
9
Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, Leiden, 2333 ZC, The Netherlands. h.van.attikum@lumc.nl.

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.

PMID:
29531219
PMCID:
PMC5847541
DOI:
10.1038/s41467-018-03484-6
[Indexed for MEDLINE]
Free PMC Article

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