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J. Biol. Chem., Vol. 282, Issue 33, 23867-23877, August 17, 2007

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RB Loss Promotes Aberrant Ploidy by Deregulating Levels and Activity of DNA Replication Factors^*

Seetha V. Srinivasan¹, Christopher N. Mayhew, Sandy Schwemberger, William Zagorski^¶, and Erik S. Knudsen²

From the Department of Cell and Cancer Biology, Vontz Center for Molecular Studies, Shriners Hospital for Children, ^¶Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267

The retinoblastoma tumor suppressor (RB) is functionally inactivated in many human cancers. Classically, RB functions to repress E2F-mediated transcription and inhibit cell cycle progression. Consequently, RB ablation leads to loss of cell cycle control and aberrant expression of E2F target genes. Emerging evidence indicates a role for RB in maintenance of genomic stability. Here, mouse adult fibroblasts were utilized to demonstrate that aberrant DNA content in RB-deficient cells occurs concomitantly with an increase in levels and chromatin association of DNA replication factors. Furthermore, following exposure to nocodazole, RB-proficient cells arrest with 4 N DNA content, whereas RB-deficient cells bypass the mitotic block, continue DNA synthesis, and accumulate cells with higher ploidy and micronuclei. Under this condition, RB-deficient cells also retain high levels of tethered replication factors, MCM7 and PCNA, indicating that DNA replication occurs in these cells under nonpermissive conditions. Exogenous expression of replication factors Cdc6 or Cdt1 in RB-proficient cells does not recapitulate the RB-deficient cell phenotype. However, ectopic E2F expression in RB-proficient cells elevated ploidy and bypassed the response to nocodazole-induced cessation of DNA replication in a manner analogous to RB loss. Collectively, these results demonstrate that deregulated S phase control is a key mechanism by which RB-deficient cells acquire elevated ploidy.

Received for publication, January 19, 2007 , and in revised form, June 1, 2007.

^* This study was supported by NCI, National Institutes of Health, Grant CA 106471 (to E. S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by NIEHS, National Institutes of Health, Grant T32 CA117846-01A1 and the Robert and Emma Lou Cardell Fellowship.

² To whom correspondence should be addressed: Dept. of Cell Biology, University of Cincinnati, Vontz Center for Molecular Studies, 3125 Eden Ave., Cincinnati, OH 45267-0521. Tel.: 513-558-8885; Fax: 513-558-4454; E-mail: Erik.knudsen{at}uc.edu.

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