In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias | Zendy

Sergio Muñoz | Zendy; Sabela Búa | Zendy; Sara RodríguezAcebes | Zendy; Diego Megı́as | Zendy; Sagrario Ortega | Zendy; Alba De Martino | Zendy; Juan Méndez | Zendy

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In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

Author(s) -

Sergio Muñoz,

Sabela Búa,

Sara RodríguezAcebes,

Diego Megı́as,

Sagrario Ortega,

Alba De Martino,

Juan Méndez

Publication year - 2017

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2017.04.032

Subject(s) - dna replication factor cdt1 , biology , dna replication , microbiology and biotechnology , origin recognition complex , control of chromosome duplication , eukaryotic dna replication , dna , genetics

Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Here, we have generated mice strains that allow the conditional overexpression of both proteins. Adult mice were unharmed by the individual overexpression of either CDC6 or CDT1, but their combined deregulation led to DNA re-replication in progenitor cells and lethal tissue dysplasias. This study offers mechanistic insights into the necessary cooperation between CDC6 and CDT1 for facilitation of origin reactivation and describes the physiological consequences of DNA overreplication.

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