biostudies-literatureLlerena Schiffmacher DAEuropean Molecular Biology OrganizationDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)NIA NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on AgingEuropean Molecular Biology Organization (EMBO)Dutch Research Council (NWO)ZonMwEuropean Joint Project on Rare Diseases RD20-113, acronym TC-NER6374https://www.ebi.ac.uk/biostudies/studies/S-EPMC11286758biostudies-literatureUnknown15(1)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 cNature communicationsThe small CRL4^CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics.PMC11286758P01 AG017242733050810714.017.003ALTF 1159-2019496650118Verlaan-de Vries MSixma TKBezstarosti KLee SHHoeijmakers JHJTheil AFvan Attikum HOgi TGonzalo-Hansen CVermeulen MAkita MVertegaal ACOMarteijn JADemmers JAAKliza KWVermeulen WLans HPines ALlerena Schiffmacher DAHelfricht AfalseThe small CRL4^CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics.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 c2024-01-01T00:00:00Z2024 Jul2026-06-03T00:17:12.879Z2025-04-04T07:43:21.524ZS-EPMC112867583907506710.1038/s41467-024-50584-7