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.

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly / Federico Tommaso, Bianchi; Chiara, Tocco; Gianmarco, Pallavicini; Yifan, Liu; Verni', Fiammetta; Merigliano, Chiara; Bonaccorsi, Silvia; Nadia El, Assawy; Lorenzo, Priano; Marta, Gai; Gaia Elena, Berto; Alessandra Maria Adelaide, Chiotto; Francesco, Sgro; Alessia, Caramello; Laura, Tasca; Ugo, Ala; Francesco, Neri; Salvatore, Oliviero; Alessandro, Mauro; Stephan, Geley; Maurizio, Gatti; Ferdinando Di, Cunto. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 18:7(2017), pp. 1674-1686. [10.1016/j.celrep.2017.01.054]

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

VERNI', Fiammetta;MERIGLIANO, CHIARA;BONACCORSI, Silvia;
2017

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.
2017
DNA damage; RAD51; TP53; apoptosis; citron kinase; cytokinesis; double strand breaks; genome instability; microcephaly
01 Pubblicazione su rivista::01a Articolo in rivista
Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly / Federico Tommaso, Bianchi; Chiara, Tocco; Gianmarco, Pallavicini; Yifan, Liu; Verni', Fiammetta; Merigliano, Chiara; Bonaccorsi, Silvia; Nadia El, Assawy; Lorenzo, Priano; Marta, Gai; Gaia Elena, Berto; Alessandra Maria Adelaide, Chiotto; Francesco, Sgro; Alessia, Caramello; Laura, Tasca; Ugo, Ala; Francesco, Neri; Salvatore, Oliviero; Alessandro, Mauro; Stephan, Geley; Maurizio, Gatti; Ferdinando Di, Cunto. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 18:7(2017), pp. 1674-1686. [10.1016/j.celrep.2017.01.054]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/933755
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