DNA checkpoints play a significant role in cancer pathology, perhaps most notably in maintaining genome stability. This review summarizes the genetic and molecular mechanisms of checkpoint activation in response to DNA damage. The major checkpoint proteins common to all eukaryotes are identified and discussed, together with how the checkpoint proteins interact to induce arrest within each cell cycle phase. Also discussed are the molecular signals that activate checkpoint responses, including single-strand DNA, double-strand breaks, and aberrant replication forks. We address the connection between checkpoint proteins and damage repair mechanisms, how cells recover from an arrest response, and additional roles that checkpoint proteins play in DNA metabolism. Finally, the connection between checkpoint gene mutation and genomic instability is considered.

Eukaryotic checkpoint genes regulate multiple cellular responses to DNA damage. In this report, we examine the roles of budding yeast genes involved in G2/M arrest and tolerance to UV exposure. A current model posits three gene classes: those encoding proteins acting on damaged DNA (e.g. RAD9 and RAD24), those transducing a signal (MEC1, RAD53 and DUN1) or those participating more directly in arrest (PDS1). Here, we define important features of the pathways subserved by those genes. MEC1, which we find is required for both establishment and maintenance of G2/M arrest, mediates this arrest through two parallel pathways. One pathway requires RAD53 and DUN1 (the 'RAD53 pathway'); the other pathway requires PDS1. Each pathway independently contributes approximately 50% to G2/M arrest, effects demonstrable after cdc13-induced damage or a double-stranded break inflicted by the HO endonuclease. Similarly, both pathways contribute independently to tolerance of UV irradiation. How the parallel pathways might interact ultimately to achieve arrest is not yet understood, but we do provide evidence that neither the RAD53 nor the PDS1 pathway appears to maintain arrest by inhibiting adaptation. Instead, we think it likely that both pathways contribute to establishing and maintaining arrest.

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FOR the most part, the surgical technics of kidney transplantation have been standardized. 3 , 8, 10, 11,11,25 The least satisfactory aspect of this operation is provision of urinary drainage as will be demonstrated by an analysis of the urologic complications encountered in 216 consecutive recipients of renal grafts at the Colorado General and Denver Veterans Administration Hospitals.The Denver series is a useful one with which to study the attributes and deficiencies of urinary drainage procedures, not only because of the large numbers of patients, but also because all operations reported were performed at least one year ago, thereby assuring reasonably long fol-