Cell Cycle-Specific Regulation of Nucleotide Excision Repair in S. Cerevisiae

点击翻译按钮获取中文摘要

Exposure to UV rays from the sun can severely damage the DNA which makes up our genes, and this can lead to the formation of genetic changes called "mutations" in our skin cells. Such mutations are highly undesirable because they represent the primary cause of malignant melanoma, an extremely deadly form of skin cancer that occurs with alarming frequency in young Canadian adults. Fortunately our cells possess a biochemical mechanism, called "Nucleotide Excision Repair" (abbreviated NER) which is able to completely reverse the damage to our genes caused by UV, thereby preventing skin cancer-causing mutations from developing in the first place. Studies from my research group previously showed for the first time that a key protein called "ATR kinase" must be present in skin cells in sufficient amounts to ensure that the NER mechanism operates efficiently. As such, our major experimental goal has been to discover precisely how ATR kinase acts to stimulate NER. However, for various technical reasons, this goal is extremely difficult to achieve using investigations on human cells. In the current grant application, we therefore propose to employ yeast cells for such studies, since these cells are far simpler to manipulate and much better characterized than human cells. More importantly yeast represents a very accurate model for studying biochemical mechanisms in humans. Indeed (i) yeast cells contain a protein called "Mec1 kinase" which works in the same way as ATR kinase in human cells and (ii) in general the yeast and human NER mechanisms bear remarkably similarity. Completion of the proposed studies would represent an important contribution to basic biological research by providing fundamental new information about how yeast cells control the NER pathway, and hence how this particular organism removes genetic damage caused by UV rays. In addition our research conducted in yeast would be expected to provide important clues regarding how the human NER process works. This will certainly benefit Canadians because, as alluded to above, NER is a major mechanism which protects humans from malignant melanoma, a dreaded disease that currently plagues our population.