Cellular DNA damage triggers the DNA damage response pathway and leads to enforcement of cell cycle checkpoints, which are essential for the maintenance of genomic integrity and are activated in early stages of tumorigenesis. A special feature of prostate cancer is its high incidence and multifocality. To address the functionality of DNA damage checkpoints in the prostate, we analyzed the responses of human primary prostate epithelial cells (HPECs) and freshly isolated human prostate tissues to ␥-irradiation. We find that ␥-irradiation activates the ataxia telangiectasia mutated-associated DNA damage response pathway in the HPECs but that the clearance of phosphorylated histone H2AX (␥H2AX) foci is delayed. Surprisingly, ␥-irradiated HPECs were unable to enforce cell cycle checkpoint arrest and had sustained cyclin-dependent kinase 2 (Cdk2)-associated kinase activity because of a lack of inhibitory Cdk phosphorylation by Wee1A tyrosine kinase. We further show that HPECs express low levels of Wee1A and that ectopic Wee1A efficiently rescues the checkpoints. We recapitulate the absence of checkpoint responses in epithelium of ex vivo irradiated human prostate tissue despite robust induction of ␥H2AX. The findings show that prostate epithelium has a surprising inability to control checkpoint arrest, the lack of which may predispose to accrual of DNA lesions.p53 ͉ irradiation ͉ cyclin-dependent kinase

The integrity of genomic DNA is challenged by genotoxic stress originating during normal cellular metabolism or by external insults. Cellular responses to DNA damage involve elegant checkpoint cascades enforcing cell cycle arrest, damage repair, apoptosis or cellular senescence. The loss or alterations of genes involved in the damage response pathways have been reported in many cancer susceptibility syndromes and in sporadic tumors. Furthermore, this surveillance pathway is activated during early tumourigenesis presumably due to uncontrolled replicative cycles and has been recognized as one of the main barriers against the development of cancer. This review discusses the relevance of prostatic epithelial cells in prostate tumourigenesis and highlights common molecular changes associated with prostate cancer. Furthermore, DNA damage responses of primary cultures of human prostatic epithelial cells and fresh human prostate tissues are discussed providing evidence for alterations in crucial DNA damage checkpoint molecules. New insights connecting prostate tumourigenesis to alterations and defects in the pathways maintaining genomic integrity will be discussed.