Browsing by Subject "Fanconi Anemia Complementation Group C Protein"

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    Fanconi anemia proteins function in mitophagy and immunity
    (Elsevier, 2016-05-05) Sumpter Jr., Rhea; Sirasanagandla, Shyam; Fernández, Álvaro F.; Wei, Yongjie; Dong, Xiaonan; Franco, Luis; Zou, Zhongju; Marchal, Christophe; Lee, Ming Yeh; Clapp, D. Wade; Hanenberg, Helmut; Levine, Beth; Department of Pediatrics, IU School of Medicine
    Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes.
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    Leukemia and chromosomal instability in aged Fancc-/- mice
    (Elsevier, 2016-05) Cerabona, Donna; Sun, Zejin; Nalepa, Grzegorz; Department of Pediatrics, IU School of Medicine
    Fanconi anemia (FA) is an inherited disorder of genomic instability associated with high risk of myelodysplasia and acute myeloid leukemia (AML). Young mice deficient in FA core complex genes do not naturally develop cancer, hampering preclinical studies on malignant hematopoiesis in FA. Here we describe that aging Fancc(-/-) mice are prone to genomically unstable AML and other hematologic neoplasms. We report that aneuploidy precedes malignant transformation during Fancc(-/-) hematopoiesis. Our observations reveal that Fancc(-/-) mice develop hematopoietic chromosomal instability followed by leukemia in an age-dependent manner, recapitulating the clinical phenotype of human FA and providing a proof of concept for future development of preclinical models of FA-associated leukemogenesis.