title: Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction.
abstract: 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.
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Supawat
authors.initials: S
authors.lastname: Thongthip
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bellani
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Siobhan Q
authors.initials: SQ
authors.lastname: Gregg
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Sunandini
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Conti
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Yanglu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Seidman
authors.affiliation: Laboratory of Genome Maintenance, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D004843:Epistasis, Genetic; D005090:Exodeoxyribonucleases / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics*; D051379:Mice; D064251:Multifunctional Enzymes; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C000596972:Fan1 protein, mouse; C498773:Mus81 protein, mouse
keywords: DNA damage; FAN1; Fanconi anemia; SNM1A; interstrand cross-link repair; karyomegalic interstitial nephritis