MITOSIS COUPLING TO COMPLETION OF DNA REPLICATION

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Chromosomes are particularly vulnerable to genetic damage while they are being replicated. If DNA is damaged, or if there are not enough nucleotides, the process of replication is halted while problems are corrected. This is unlikely to be due to a physical block to DNA replication, rather complex mechanisms involving cell cycle control and DNA repair ensure that S-phase arrest and recovery take place in an orderly fashion. By preventing genetic changes during replication, the mechanisms underlying S-phase arrest and recovery play an important role in preventing cancer. Moreover, since inhibitors of S-phase are frequently used in chemotherapy, understanding the cellular basis of S-phase arrest and recovery is of considerable health relevance. We have been studying 5-phase arrest and recovery using the fission yeast, Schizosaccharomyces pombe. Like the more commonly studied yeast, Saccharomyces cerevisiae, S. pombe can be conveniently studied using a range of powerful molecular and genetic techniques. We have identified mutants that have defects in 5-phase arrest and recovery by screening for mutants that undergo abnormal mitoses upon treatment with hydroxyurea (HU), an inhibitor DNA synthesis. Two of the genes we have identified are related to human genes mutated in cancer-prone syndromes. Rad3+ is required for S-phase arrest and is related to the ATM gene, deficient in patients suffering from Ataxia-Telangiectasia (A-T). hus2+ is required for recovery from S-phase arrest and is related to BLM, the gene mutated in patients afflicted with Blooms Syndrome (BS). A-T and BS patients display a range of complex symptoms, including a significantly increased risk for a range of cancers. To better understand the cellular processes preventing cancer, we are proposing to analyze rad3+, hus2+ and other genes required for S- phase arrest and recovery.