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Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5'-3' exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit(+) cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.
Pubmed ID: 26980189
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Center that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine function of every gene in mouse genome. These mice will be preserved in repositories and made available to scientific community representing valuable resource for basic scientific research as well as generating new models for human diseases.
View all literature mentionsA contract research organization providing drug development and animal testing services. Under the name Covance Research Products Inc., based in Denver, Pennsylvania, the company also deals in the import, breeding and sale of laboratory animals. It breeds dogs, rabbits, guinea pigs, non-human primates, and pigs, and runs the largest non-human primate laboratory in Germany. (Wikipedia)
View all literature mentions3D image analysis software to visualize, analyze and validate 3D fluorescence images from a wide range of confocal microscopy, widefield and high content screening systems. It is fully integrated for a seamless user experience.
View all literature mentionsRepository of mouse vectors, ES cells, mice, embryos, and sperm generated by NIH KOMP Mutagenesis Project. In addition, KOMP Repository offers services in support of KOMP products, including ES cell microinjection, vector cloning, post-insertional modification of cloned ES cells, cryopreservation, assisted reproduction techniques (IVF, ICSI) and mouse breeding, pathology services, phenotyping services, etc. KOMP Repository is final component of more than $50 million trans-NIH initiative to increase availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children''s Hospital Oakland Research Institute (CHORI) in Oakland, Calif., are collaborating to preserve, protect, and make available about 8,500 types of knockout mice and related products available to research community. Products are generated by two KOMP mutagenesis teams (CSD consortium and Regeneron Inc). All KOMP products generated by CSD consortium and Regeneron are available through KOMP Repository. Notice as of December 19, 2019: Materials from KOMP Repository have been deposited into MMRRC, including all mouse models and mouse embryonic stem cell lines. Eventually www.komp.org will be sunsetting, and IMSR will remove KOMP Repository listings, since they were double listed in MMRRC. MMRRC will contain the most accurate and up to date resource models.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name B6.FVB-Tg(EIIa-cre)C5379Lmgd/J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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