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Functional comparison of XPF missense mutations associated to multiple DNA repair disorders
Marín, Maria (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Ramírez de Haro, Ma. José (María José) (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Aza-Carmona, Miriam (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Jia, Nan (Nagoya University. Research Institute of Environmental Medicine)
Ogi, Tomoo (Nagoya University. Research Institute of Environmental Medicine)
Bogliolo, Massimo (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Date: 2019
Abstract: XPF endonuclease is one of the most important DNA repair proteins. Encoded by XPF/ERCC4, XPF provides the enzymatic activity of XPF-ERCC1 heterodimer, an endonuclease that incises at the 5’ side of various DNA lesions. XPF is essential for nucleotide excision repair (NER) and interstrand crosslink repair (ICLR). XPF/ERCC4 mutations are associated with several human diseases: Xeroderma Pigmentosum (XP), Segmental Progeria (XFE), Fanconi Anemia (FA), Cockayne Syndrome (CS), and XP/CS combined disease (XPCSCD). Most affected individuals are compound heterozygotes for XPF/ERCC4 mutations complicating the identification of genotype/phenotype correlations. We report a detailed overview of NER and ICLR functional studies in human XPF-KO (knock-out) isogenic cells expressing six disease-specific pathogenic XPF amino acid substitution mutations. Ultraviolet (UV) sensitivity and unscheduled DNA synthesis (UDS) assays provide the most reliable information to discern mutations associated with ICLR impairment from mutations related to NER deficiency, whereas recovery of RNA synthesis (RRS) assays results hint to a possible role of XPF in resolving R-loops. Our functional studies demonstrate that a defined cellular phenotype cannot be easily correlated to each XPF mutation. Substituted positions along XPF sequences are not predictive of cellular phenotype nor reflect a particular disease. Therefore, in addition to mutation type, allelic interactions, protein stability and intracellular distribution of mutant proteins may also contribute to alter DNA repair pathways balance leading to clinically distinct disorders.
Note: Número d'acord de subvenció MINECO/CB06-07-0023
Note: Número d'acord de subvenció MINECO/SAF2015-64152-R
Note: Número d'acord de subvenció EC/FP7/305421
Note: Número d'acord de subvenció MECD/FPU2013-00754
Note: Número d'acord de subvenció MICINN/JCI2011-10660
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Subject: XPF-KO ; XPF/ERCC4 mutations ; DNA repair ; Genotype-phenotype correlation
Published in: Genes, Vol. 10, Núm. 1 (January 2019) , art. 60, ISSN 2073-4425

DOI: 10.3390/genes10010060
PMID: 30658521


14 p, 745.8 KB

The record appears in these collections:
Articles > Research articles
Articles > Published articles

 Record created 2019-01-30, last modified 2019-05-13



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