title: FANCA safeguards interphase and mitosis during hematopoiesis in vivo.
abstract: The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA-/- cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zahi
authors.initials: Z
authors.lastname: Abdul-Sater
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Donna
authors.initials: D
authors.lastname: Cerabona
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Elizabeth Sierra
authors.initials: ES
authors.lastname: Potchanant
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zejin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Rikki
authors.initials: R
authors.lastname: Enzor
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Kent
authors.initials: K
authors.lastname: Robertson
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Goebel
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; Bone Marrow Failure Program, Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indianapolis, Indiana. Electronic address: gnalepa@iu.edu.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
mesh_terms: D000818:Animals; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D007399:Interphase; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C498471:FANCA protein, human; C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein