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

Alba Muniesa-Vargas, Carlota Davó-Martínez, Cristina Ribeiro-Silva, Melanie van der Woude, Karen L. Thijssen, Ben Haspels, David Häckes, Ülkem U. Kaynak, Roland Kanaar, Jurgen A. Marteijn, Arjan F. Theil, Maayke M. P. Kuijten, Wim Vermeulen and Hannes Lans ()
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Alba Muniesa-Vargas: Erasmus University Medical Center
Carlota Davó-Martínez: Erasmus University Medical Center
Cristina Ribeiro-Silva: Erasmus University Medical Center
Melanie van der Woude: Erasmus University Medical Center
Karen L. Thijssen: Erasmus University Medical Center
Ben Haspels: Erasmus University Medical Center
David Häckes: Erasmus University Medical Center
Ülkem U. Kaynak: Erasmus University Medical Center
Roland Kanaar: Erasmus University Medical Center
Jurgen A. Marteijn: Erasmus University Medical Center
Arjan F. Theil: Erasmus University Medical Center
Maayke M. P. Kuijten: Erasmus University Medical Center
Wim Vermeulen: Erasmus University Medical Center
Hannes Lans: Erasmus University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47935-9

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