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Our major focus is to understand the molecular mechanisms involved in maintaining genome integrity during chromosome replication. Our current research programs are:<br/><br/>(1). We investigate what types of mutation in genes that play a critical role in DNA replication can cause an early event in tumorigenesis and are a source of the genetic instability observed in cancer cells. We use both budding and fission yeast as the model organisms to identify replication mutators. Similar and identical mutations are then introduced into homologues genes in human cell lines. We then investigate the physiological effects of the replication mutators on human cells by cytogenetic, cell biologic, and biochemical approaches to resolve the molecular mechanisms that cause the aberrant phenotype in human cells.<br/><br/>(2). We investigate how cells respond to replication stress to maintain genome integrity by checkpoint mechanisms. We used fission yeast as the model organism and replication mutants to induce stress in S-phase. We then investigate how the checkpoint mechanisms maintain genome integrity by inducing tolerance of the replication stress, preventing replication fork collapse, and promoting replication fork re-start. Knowledge gained from the fission yeast studies is then apply to investigate how mammalian cells respond to replication stress to maintain genome integrity.