Persistent TFIIH binding to non-excised DNA damage causes cell and developmental failure

• Published in: Nature communications Vol. 15; no. 1; p. 3490
• Main Authors: Muniesa-Vargas, Alba, Davó-Martínez, Carlota, Ribeiro-Silva, Cristina, van der Woude, Melanie, Thijssen, Karen L, Haspels, Ben, Häckes, David, Kaynak, Ülkem U, Kanaar, Roland, Marteijn, Jurgen A, Theil, Arjan F, Kuijten, Maayke M P, Vermeulen, Wim, Lans, Hannes
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.04.2024; Nature Portfolio
• Subjects: Aetiology; Animals; Binding; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cancer; Damage; Deoxyribonucleic acid; Disorders; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endonucleases - genetics; Endonucleases - metabolism; ERCC1 protein; Humans; Intermediates; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleotide excision repair; Nucleotides; Phenotypes; Protein Binding; Senescence; Transcription; Transcription Factor TFIIH - genetics; Transcription Factor TFIIH - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Xeroderma Pigmentosum Group A Protein - genetics; Xeroderma Pigmentosum Group A Protein - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47935-9

Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the absence of functional ERCC1-XPF or XPG endonucleases leads to stable and prolonged binding of the transcription/DNA repair factor TFIIH to DNA damage, which correlates with disease severity and induces senescence features in human cells. In vivo, in C. elegans, this prolonged TFIIH binding to non-excised DNA damage causes developmental arrest and neuronal dysfunction, in a manner dependent on transcription-coupled NER. NER factors XPA and TTDA both promote stable TFIIH DNA binding and their depletion therefore suppresses these severe phenotypical consequences. These results identify stalled NER intermediates as pathogenic to cell functionality and organismal development, which can in part explain why mutations in XPF or XPG cause different disease features than mutations in XPA or TTDA.