ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients
Loading...
Citations
Scopus:
Altmetric:
Altmetric::
Download
Associated Records
Authors
File Licence
Editors
Date
2021-01-01
Source Title
Journal of Experimental Medicine (JEM)
Journal Title
Journal ISSN
Volume Title
Publisher
ROCKEFELLER UNIV PRESS
Melbourne Authors
Affiliation
Paediatrics (RCH)
Clinical Pathology
Clinical Pathology
Document Type
Journal Article
Subject Code
Citation
Apelt, K., White, S. M., Kim, H. S., Yeo, J. E., Kragten, A., Wondergem, A. P., Rooimans, M. A., González-Prieto, R., Wiegant, W. W., Lunke, S., Flanagan, D., Pantaleo, S., Quinlan, C., Hardikar, W., van Attikum, H., Vertegaal, A. C. O., Wilson, B. T., Wolthuis, R. M. F., Schärer, O. D. & Luijsterburg, M. S. (2021). ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients. Journal of Experimental Medicine, 218 (3), https://doi.org/10.1084/JEM.20200622.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
Abstract
ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.