Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype

Fanconi anemia (FA) is a human genetic disease characterized by chromosome instability, cancer predisposition, and cellular hypersensitivity to DNA crosslinking agents. The FA pathway regulates the repair of DNA crosslinks. A critical step in this pathway is the monoubiquitination and deubiquitinati...

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Veröffentlicht in:Developmental cell Jg. 16; H. 2; S. 314
Hauptverfasser: Kim, Jung Min, Parmar, Kalindi, Huang, Min, Weinstock, David M, Ruit, Carrie Ann, Kutok, Jeffrey L, D'Andrea, Alan D
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.02.2009
Schlagworte:
Animals
Arabidopsis Proteins
Crosses, Genetic
DNA Repair
Endopeptidases - genetics
Endopeptidases - physiology
Fanconi Anemia - genetics
Fanconi Anemia Complementation Group D2 Protein - metabolism
Female
Fibroblasts - metabolism
Gene Deletion
Genomic Instability
Lymphocytes - metabolism
Male
Mice
Mice, Knockout
Phenotype
Ubiquitin-Specific Proteases
ISSN:1878-1551, 1878-1551
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Zusammenfassung:Fanconi anemia (FA) is a human genetic disease characterized by chromosome instability, cancer predisposition, and cellular hypersensitivity to DNA crosslinking agents. The FA pathway regulates the repair of DNA crosslinks. A critical step in this pathway is the monoubiquitination and deubiquitination of FANCD2. Deubiquitination of FANCD2 is mediated by the ubiquitin protease, USP1. Here, we demonstrate that targeted deletion of mouse Usp1 results in elevated perinatal lethality, male infertility, crosslinker hypersensitivity, and an FA phenotype. Usp1(-/-) mouse embryonic fibroblasts had heightened levels of monoubiquitinated Fancd2 in chromatin. Usp1(-/-) cells exhibited impaired Fancd2 foci assembly and a defect in homologous recombination repair. Double knockout of Usp1 and Fancd2 resulted in a more severe phenotype than either single knockout. Our results indicate that mouse Usp1 functions downstream in the FA pathway. Deubiquitination is a critical event required for Fancd2 nuclear foci assembly, release from chromatin, and function in DNA repair.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1878-1551
1878-1551
DOI:10.1016/j.devcel.2009.01.001