title: Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly.
abstract: Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy. Electronic address: federico.bianchi@unito.it.
authors.forename: Federico Tommaso
authors.initials: FT
authors.lastname: Bianchi
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tocco
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Pallavicini
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University, 00185 Rome, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Vernì
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University, 00185 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Merigliano
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University, 00185 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonaccorsi
authors.affiliation: Department of Neurology and Neurorehabilitation, San Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, 28824 Piancavallo (VB), Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: El-Assawy
authors.affiliation: Department of Neurology and Neurorehabilitation, San Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, 28824 Piancavallo (VB), Italy; Department of Neuroscience, University of Torino, 10126 Torino, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Priano
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Gai
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy.
authors.forename: Gaia Elena
authors.initials: GE
authors.lastname: Berto
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy.
authors.forename: Alessandra Maria Adelaide
authors.initials: AM
authors.lastname: Chiotto
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sgrò
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Caramello
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tasca
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Department of Neurology and Neurorehabilitation, San Giuseppe Hospital, Istituto Auxologico Italiano IRCCS, 28824 Piancavallo (VB), Italy; Department of Neuroscience, University of Torino, 10126 Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University, 00185 Rome, Italy; Institute of Molecular Biology and Pathology (IBPM), CNR, 00185 Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gatti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano (TO), Italy. Electronic address: ferdinando.dicunto@unito.it.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Di Cunto
mesh_terms: D000818:Animals; D043171:Chromosomal Instability / Q000235:genetics*; D048749:Cytokinesis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008322:Mammals / Q000235:genetics; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D051135:Rad51 Recombinase / Q000235:genetics; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases; D051135:Rad51 Recombinase
keywords: DNA damage; RAD51; TP53; apoptosis; citron kinase; cytokinesis; double strand breaks; genome instability; microcephaly