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Kim, Hyun Suk
유전체 항상성 연구단
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ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

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Title
ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients
Author(s)
Apelt, Katja; White, Susan M.; Hyun Suk Kim; Jung-Eun Yeo; Kragten, Angela; Wondergem, Annelotte P.; Rooimans, Martin A.; González-Prieto, Román; Wiegant, Wouter W.; Lunke, Sebastian; Flanagan, Daniel; Pantaleo, Sarah; Quinlan, Catherine; Hardikar, Winita; van Attikum, Haico; Vertegaal, Alfred C O; Wilson, Brian T.; Wolthuis, Rob M F; Orlando D. Schärer; Luijsterburg, Martijn S.
Publication Date
2021-03
Journal
Journal of Experimental Medicine, v.218, no.3, pp.1 - 25
Publisher
Rockefeller University Press
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.
URI
https://pr.ibs.re.kr/handle/8788114/9207
DOI
10.1084/jem.20200622
ISSN
0022-1007
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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