Cell Cycle Checkpoint in Response to DNA Damage

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Cell cycle checkpoints ensure the integrity of the genome from one replicative cell cycle to the next. In the event of catastrophic damage to the genome, cells of multicellular eukaryotes can undergo apoptosis, _resumably to eliminate them from the cell population and reduce the risk of propagating genetically Jnstable cells. Alternatively, cells may respond to DNA damage by undergoing a transient arrest of the cell =ycle, which correlates with their ability to survive exposure to DNA damaging agents. This response requires the DNA damage checkpoint pathway; if compromised by mutation or drug treatment, cells will enter "nitosiswith damaged DNA and die. The fission yeast has been an extremely valuable system for identifying and characterizing components of the DNA damage checkpoint. Indeed, many proteins that are now known to function in the checkpoint pathway in mammalian cells were identified solely based on their sequence homology to proteins that were identified genetically and functionally in yeast. Thus, it is clear that the identification of proteins in yeast using the power of classical genetics is a valid and productive means of identifying and gaining insight into the function of mammalian counterparts. Experiments described in this proposal will continue to investigate the protein kinase, Chkl, a key regulator of the checkpoint in eukaryotic cells. In addition, we will focus on a novel fission yeast protein, Mscl. Mscl shares structural domain homology with mammalian RbBP2, a protein identified by virtue of its ability to bind the tumor suppressor 3rotein Rb and with PLU-1, the product of a gene that is up regulated in breast cancer cells. Mscl was ',loned because it can compensate for the loss of function Chkl. The Mscl protein appears to be important or histone modifications of chromatin, for genomic stability and for survival after DNA damage. Experiments described in this proposal aim to dissect the role of the Mscl protein in fission yeast, to lay the groundwork for understanding the functions of the human homologues.