ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients.
Alleles
Amino Acid Substitution
Base Sequence
Cell Line
Cytoplasm
/ metabolism
DNA Breaks, Double-Stranded
DNA Damage
/ genetics
DNA Repair
/ genetics
DNA-Binding Proteins
/ deficiency
Endonucleases
/ deficiency
Fibroblasts
/ metabolism
Humans
Kidney
/ pathology
Light
Liver
/ pathology
Mutant Proteins
/ metabolism
Mutation
/ genetics
Mutation, Missense
/ genetics
Protein Stability
Siblings
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
03
04
2020
revised:
25
09
2020
accepted:
15
10
2020
entrez:
14
12
2020
pubmed:
15
12
2020
medline:
15
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33315086
pii: 211590
doi: 10.1084/jem.20200622
pmc: PMC7927433
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Mutant Proteins
0
xeroderma pigmentosum group F protein
0
ERCC1 protein, human
EC 3.1.-
Endonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 310913
Pays : International
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218315
Pays : United States
Informations de copyright
© 2020 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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