Prolla 9803534 DNA repair plays an essential role in the maintenance of genomic stability in response to both endogenous and environmental insults. Although many proteins that play a direct role in repair have been characterized, little is known regarding how cells sense DNA damage and elicit a damage response. A serine/threonine protein kinase identified in Saccharomyces cereviseae appears to be involved in DNA repair, perhaps in a signal transduction cascade that senses the presence of unrepaired DNA. A family of mammalian serine/threonine kinases, CKI, has been purified and demonstrated to be highly homologous to the yeast enzyme. Two of the isoforms have been demonstrated to complement the yeast mutants and to show the most homology to the yeast enzyme. Embryonic stem cells and mice deficient for three of the isoforms have been generated and will be used to determine the role of these genes in the response to X-rays and other DNA damaging agents. The genetic characterization of the mammalian CKI gene family will continue by the use of gene targeting in the mouse. The use of yeast as a model system will continue as an approach to identification of other components of the signaling pathway. An understanding of DNA repair mechanisms utilized by mammals is of obvious importance for basic and practical reasons. This study should contribute to that understanding.
