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
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Department of Molecular Genetics, Erasmus MC Cancer Institute, Oncode Institute, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Nat Commun. 2024 Apr 25;15(1):3490. 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.
先天性核苷酸切除修复（NER）缺陷会引发多种易患癌症和/或早衰样疾病。目前尚不清楚同一DNA修复途径中的缺陷如何导致不同的疾病特征和严重程度。在此，我们表明功能性ERCC1-XPF或XPG核酸内切酶的缺失会导致转录/DNA修复因子TFIIH与DNA损伤稳定且长时间结合，这与疾病严重程度相关，并在人类细胞中诱导衰老特征。在体内，在秀丽隐杆线虫中，TFIIH与未切除的DNA损伤的这种长时间结合会导致发育停滞和神经元功能障碍，其方式依赖于转录偶联的NER。NER因子XPA和TTDA均促进TFIIH与DNA的稳定结合，因此它们的缺失会抑制这些严重的表型后果。这些结果表明停滞的NER中间体对细胞功能和机体发育具有致病性，这可以部分解释为什么XPF或XPG中的突变与XPA或TTDA中的突变会导致不同的疾病特征。
