RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo
| Autor: | Ryan J. Bourgo, Ursula Ehmer, Erik S. Knudsen, Julien Sage |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
DNA Replication
DNA damage Mitosis Eukaryotic DNA replication Mice Transgenic Retinoblastoma Protein DNA replication factor CDT1 Mice Replication factor C Cyclin D1 Control of chromosome duplication Animals Cyclin B1 E2F Molecular Biology Ploidies biology Cell Cycle DNA replication Cell Biology Articles Molecular biology E2F Transcription Factors Liver biology.protein Gene Deletion DNA Damage |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 |
| Popis: | The retinoblastoma tumor suppressor (RB) is functionally inactivated at high frequency in nearly all tumor types. Herein the acute deletion of RB in the liver reveals an immediate and profound dysregulation of spatiotemporal coordination in cell-cycle phases, resulting in robust DNA damage and aneuploidy that is not found in other tissues. The integrity of the retinoblastoma tumor suppressor (RB) pathway is critical for restraining inappropriate proliferation and suppressing tumor development in a plethora of tissues. Here adenovirus-mediated RB deletion in the liver of adult mice led to DNA replication in the absence of productive mitotic condensation. The replication induced by RB loss was E2F-mediated and associated with the induction of DNA damage and a nontranscriptional G2/M checkpoint that targeted the accumulation of Cyclin B1. In the context of RB deletion or E2F activation, there was an increase in hepatocyte ploidy that was accompanied by hyperphysiological assembly of prereplication complexes. In keeping with this dysregulation, initiation of DNA replication was readily observed in hepatocytes that were phenotypically in G2/M. Under such conditions, uncoupling of replication initiation from mitotic progression led to altered genome ploidy in the liver. Interestingly, these findings in hepatocytes were not recapitulated in the basally proliferative tissues of the gastrointestinal tract, where RB deletion, while increasing DNA replication, did not lead to a profound uncoupling from mitosis. Combined, these findings demonstrate the critical role of RB in controlling cell-cycle transitions and underscore the importance of intrinsic tissue environments in resultant phenotypes. |
| Databáze: | OpenAIRE |
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