The small CRL4 CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics.

Autor: Llerena Schiffmacher DA; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Lee SH; Division of Biochemistry and Oncode institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Kliza KW; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, 6525 GA, Nijmegen, the Netherlands.; Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany., Theil AF; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Akita M; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore., Helfricht A; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Bezstarosti K; Proteomics Center, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Gonzalo-Hansen C; Department of Molecular Genetics, Erasmus MC Cancer Institute, Oncode Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., van Attikum H; Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands., Verlaan-de Vries M; Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands., Vertegaal ACO; Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands., Hoeijmakers JHJ; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.; University Hospital of Cologne, CECAD Forschungszentrum, Institute for Genome Stability in Aging and Disease, Joseph Stelzmann Strasse 26, 50931, Köln, Germany.; Princess Maxima Center for Pediatric Oncology, Oncode Institute, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands., Marteijn JA; Department of Molecular Genetics, Erasmus MC Cancer Institute, Oncode Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Lans H; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Demmers JAA; Proteomics Center, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Vermeulen M; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, 6525 GA, Nijmegen, the Netherlands.; Division of Molecular Genetics and Oncode institute, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, the Netherlands., Sixma TK; Division of Biochemistry and Oncode institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Ogi T; Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Nagoya, Japan.; Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan., Vermeulen W; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands. w.vermeulen@erasmusmc.nl., Pines A; Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands. a.pines@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 29; Vol. 15 (1), pp. 6374. Date of Electronic Publication: 2024 Jul 29.
DOI: 10.1038/s41467-024-50584-7
Abstrakt: Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4 CSA ). Although ubiquitination of several TC-NER proteins by CRL4 CSA has been reported, it is still unknown how this complex is regulated. To unravel the dynamic molecular interactions and the regulation of this complex, we apply a single-step protein-complex isolation coupled to mass spectrometry analysis and identified DDA1 as a CSA interacting protein. Cryo-EM analysis shows that DDA1 is an integral component of the CRL4 CSA complex. Functional analysis reveals that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process.
(© 2024. The Author(s).)
Databáze: MEDLINE
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