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)

Data:	2019
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad CB06-07-0023 Ministerio de Economía y Competitividad SAF2015-64152-R European Commission 305421 Ministerio de Educación, Cultura y Deporte FPU2013-00754 Ministerio de Ciencia e Innovación JCI2011-10660
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	XPF-KO ; XPF/ERCC4 mutations ; DNA repair ; Genotype-phenotype correlation
Publicat a:	Genes, Vol. 10, Núm. 1 (January 2019) , art. 60, ISSN 2073-4425

DOI: 10.3390/genes10010060
PMID: 30658521

14 p, 745.8 KB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats