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Cell Rep. 2017 May 2;19(5):928-938. doi: 10.1016/j.celrep.2017.04.032.

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias.

Author information

1
DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
2
Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
3
Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
4
Compared Pathology Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
5
DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain. Electronic address: jmendez@cnio.es.

Abstract

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.

KEYWORDS:

CDC6; CDT1; DNA replication; replication origin; tissue dysplasia

PMID:
28467906
DOI:
10.1016/j.celrep.2017.04.032
[Indexed for MEDLINE]
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