Federico, Giorgia (2016) NCOA4 impairs systemic iron homeostasis. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: NCOA4 impairs systemic iron homeostasis
Autori:
AutoreEmail
Federico, Giorgiagiorgia.federico@libero.it
Data: 30 Marzo 2016
Numero di pagine: 71
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricovittorioenrico.avvedimento@unina.it
Tutor:
nomeemail
Carlomagno, Francesca[non definito]
Data: 30 Marzo 2016
Numero di pagine: 71
Parole chiave: NCOA4 Ferritinophagy DNA Replication
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 13 Apr 2016 10:45
Ultima modifica: 05 Mag 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/10872

Abstract

NCOA4 protein is involved in iron metabolism. Indeed, under low iron conditions, NCOA4 accumulates and promotes, as cargo receptor, the autophagic degradation of the iron-storage macromolecule ferritin. This process, called ferritinophagy, is critical to restore the appropriate cellular iron levels and could impair systemic iron homeostasis. Consistently, we have demonstrated that mice carrying genetic ablation of NCOA4 were unable to mobilize iron from deposits, featuring tissue iron overload as well as mild anemia. Because of impaired ferritinophagy, NCOA4 null mice displayed a severe mycrocitic hypocromic anemia and ineffective erythropoiesis when fed with an iron low diet. Conversely, they poorly tolerated an iron rich diet, dying prematurely for iron toxicity. Since in previous studies we discovered that nuclear NCOA4 is a chromatin binding protein that acts as a negative regulator of DNA replication origin activation, inhibiting the MCM2-7 DNA helicase, we also investigated whether NCOA4 could regulate DNA replication as a function of iron bioavailability. Treatment with iron chelators promoted a G1-arrest, blocking DNA replication origins activation. In cell fractionation experiments, we observed that iron depletion induced nuclear translocation of NCOA4, and by ChIP and co-immunoprecipitation assays we demonstrated that NCOA4 increased its binding to DNA replication origins and to MCM2-7 complex, respectively. Silencing of NCOA4 induced an unscheduled activation of DNA replication under iron-depleted conditions that promotes replication stress and reduction of cell viability. In conclusion, our data indicate NCOA4 as a novel inter player coupling DNA replication origin activation to cellular iron levels.

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