The small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics

Diana A. Llerena Schiffmacher, Shun-Hsiao Lee, Katarzyna W. Kliza, Arjan F. Theil, Masaki Akita, Angela Helfricht, Karel Bezstarosti, Camila Gonzalo-Hansen, Haico Attikum, Matty Verlaan- de Vries, Alfred C. O. Vertegaal, Jan H. J. Hoeijmakers, Jurgen A. Marteijn, Hannes Lans, Jeroen A. A. Demmers, Michiel Vermeulen, Titia K. Sixma, Tomoo Ogi, Wim Vermeulen () and Alex Pines ()
Additional contact information
Diana A. Llerena Schiffmacher: Erasmus University Medical Center
Shun-Hsiao Lee: Netherlands Cancer Institute
Katarzyna W. Kliza: Radboud University Nijmegen
Arjan F. Theil: Erasmus University Medical Center
Masaki Akita: Erasmus University Medical Center
Angela Helfricht: Erasmus University Medical Center
Karel Bezstarosti: Erasmus University Medical Center
Camila Gonzalo-Hansen: Erasmus University Medical Center
Haico Attikum: Leiden University Medical Center
Matty Verlaan- de Vries: Leiden University Medical Center
Alfred C. O. Vertegaal: Leiden University Medical Center
Jan H. J. Hoeijmakers: Erasmus University Medical Center
Jurgen A. Marteijn: Erasmus University Medical Center
Hannes Lans: Erasmus University Medical Center
Jeroen A. A. Demmers: Erasmus University Medical Center
Michiel Vermeulen: Radboud University Nijmegen
Titia K. Sixma: Netherlands Cancer Institute
Tomoo Ogi: Nagoya University
Wim Vermeulen: Erasmus University Medical Center
Alex Pines: Erasmus University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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 (CRL4CSA). Although ubiquitination of several TC-NER proteins by CRL4CSA 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 CRL4CSA complex. Functional analysis reveals that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process.

Date: 2024
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DOI: 10.1038/s41467-024-50584-7

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