Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia

BFanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic ba...

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Authors: Bogliolo, Massimo|||0000-0001-8240-7784, Schuster, Beatrice, Stoepker, Chantal, Derkunt, Burak, Su, Yan, Raams, Anja, Trujillo Quintero, Juan Pablo, Minguillón Pedreño, Jordi|||0000-0003-2124-8294, Ramírez de Haro, Ma. José|||0000-0003-1417-7731, Pujol Calvet, Maria Roser|||0000-0003-1840-5455, Casado, José A.|||0000-0003-2479-1508, Baños, Rocío, Río, Paula, Knies, Kerstin, Zúñiga, Sheila, Benitez, Javier|||0000-0002-0923-7202, Bueren, Juan|||0000-0002-3228-7013, Jaspers, Nicolaas G. J., Schärer, Orlando D., Winter, Johan P. de, Schindler, Detlev, Surralles, Jordi|||0000-0002-4041-7519
Format: article
Publication Date:2013
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:132517
Online Access:https://ddd.uab.cat/record/132517
https://dx.doi.org/urn:doi:10.1016/j.ajhg.2013.04.002
Access Level:Open access
Keyword:Fanconi anemia
DNA
Description
Summary:BFanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.

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