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In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias
Sergio Muñoz1, Sabela Búa1, Sara Rodríguez-Acebes1
1DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
Cell Reports
|May 4, 2017
Summary
Overexpressing CDC6 and CDT1 proteins together in mice caused DNA overreplication and tissue damage, revealing their cooperative role in preventing DNA overreplication.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Mammalian DNA replication origins require licensing by DNA helicases, a process mediated by CDC6 and CDT1 proteins.
- CDC6 and CDT1 are inhibited after DNA synthesis initiation to prevent DNA overreplication before cell division.
- High expression of CDC6 and CDT1 is observed in cancer cells, but their in vivo impact was unknown.
Purpose of the Study:
- To investigate the in vivo consequences of deregulated CDC6 and CDT1 expression.
- To understand the cooperative role of CDC6 and CDT1 in DNA replication origin reactivation.
- To explore the physiological effects of DNA overreplication.
Main Methods:
- Generation of mouse strains with conditional overexpression of CDC6 and CDT1.
- Assessment of adult mice following individual or combined overexpression of CDC6 and CDT1.
- Analysis of DNA re-replication and tissue pathology in progenitor cells.
Main Results:
- Individual overexpression of CDC6 or CDT1 in adult mice caused no harm.
- Combined overexpression of CDC6 and CDT1 led to DNA re-replication in progenitor cells.
- Combined deregulation resulted in lethal tissue dysplasias.
Conclusions:
- CDC6 and CDT1 cooperate to facilitate DNA replication origin reactivation.
- Deregulation of CDC6 and CDT1 can lead to DNA overreplication and severe tissue pathology.
- This study provides mechanistic insights into DNA replication control and its physiological consequences.
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