¹Department of Hematology and Oncology, Albert-Ludwigs University Medical Center, Freiburg, Germany

Correspondence: Dr R Wäsch, Department of Hematology and Oncology, Albert-Ludwigs University Medical Center, Hugstetter Street 55, Freiburg D-79106, Germany. E-mail: ralph.waesch@uniklinik-freiburg.de

Received 22 January 2007; Revised 14 May 2007; Accepted 3 July 2007; Published online 13 August 2007.

Abstract

Ensuring precise DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. Proteolytic control of cell cycle regulators by the anaphase-promoting complex, activated by Cdh1 (APC^Cdh1), is responsible for a stable G₁ phase after mitotic exit allowing accurate preparation for DNA replication in the following S phase. APC^Cdh1 target proteins are frequently upregulated in tumor cells and the inactivation of human Cdh1 might interfere with genome integrity by target stabilization. Here we show that APC^Cdh1 is required for maintaining genomic integrity in primary human cells. Lentiviral-delivered strong and stable suppression of Cdh1 by RNA interference (RNAi) causes aberrant accumulation of several APC^Cdh1 target proteins, such as cyclin A, B, Aurora A or Plk1, which control accurate and equal distribution of the genetic information to daughter cells. This induces a premature and prolonged S phase, mitotic-entry delay and defects in chromosome separation and cytokinesis. Cell cycle deregulation by stable knockdown of Cdh1 leads to activation of p53/p21 and genomic instability, which is further increased by codepletion of p53. Thus, stabilization of APC^Cdh1 targets may initiate aberrant DNA replication and chromosome separation, and trigger a p53 response by deregulating G₁ in primary human cells.