RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo

Ryan J. Bourgo, Ursula Ehmer, Julien Sage, Erik S. Knudsen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)931-939
Number of pages9
JournalMolecular Biology of the Cell
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2011

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DNA Replication
Hepatocytes
Ploidies
Cyclin B1
Critical Pathways
Retinoblastoma
Liver
Mitosis
Adenoviridae
DNA Damage
Gastrointestinal Tract
Neoplasms
Cell Cycle
Genome
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo. / Bourgo, Ryan J.; Ehmer, Ursula; Sage, Julien; Knudsen, Erik S.

In: Molecular Biology of the Cell, Vol. 22, No. 7, 01.04.2011, p. 931-939.

Research output: Contribution to journalArticle

Bourgo, Ryan J. ; Ehmer, Ursula ; Sage, Julien ; Knudsen, Erik S. / RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo. In: Molecular Biology of the Cell. 2011 ; Vol. 22, No. 7. pp. 931-939.
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