RIVIER, David H.

Departments of Cell & Structural Biology and Microbiology
Ph.D. (1988) University of Oregon, Eugene

   Research Topics

• Molecular Mechanisms Regulating Eukaryotic Chromosomal Replication
• Identification and Characterization of Chromosomal Origins of Replication
• Molecular Mechanisms of Position Effects
• Yeast Molecular Genetics

   Research Interests  

   My laboratory focuses on two regulatory aspects of DNA replication - the regulation of initiation of chromosomal replication and the possible regulation of transcription by DNA replication.

   DNA replication is perhaps the most precisely regulated protein-nucleic acid interaction in biology; each base in the genome is replicated once and only once every cell cycle. Much of this regulation is likely to occur at origins. Enough origins must fire every cell cycle for each chromosome to be completely replicated while reinitiation at every origin must be prevented. Little is known about the molecular mechanisms that control initiation of eukaryotic DNA replication because chromosomal origins are ill defined.

   We have recently identified a chromosomal origin of replication and partially defined the sequences required for initiation. The sequences that comprise the origin are the exact same sequences that constitute a previously identified regulatory element known as the HMR-E silencer. This silencer-origin regulates transcription, recombination, endonuclease cleavage and other protein-nucleic acid interactions throughout a region of the chromosome. Such regional control of chromosomal behavior is analogous to the classical genetic phenomenon known as "position effects". Our demonstration that a silencer is a chromosomal origin raises the intriguing possibility that DNA replication itself can alter the genetic properties of chromosomal regions.

   We are taking a classically and manipulative molecular genetic approach to identify the cellular machinery required for initiation of DNA replication and silencer-dependent position effects. We expect this analysis to lead to an understanding of regulated initiation of DNA replication, how replication is coupled to the cell cycle and the relationship between DNA replication and chromosomal position effects. The machinery that regulates DNA replication is a reasonable target for development of anti-cancer and anti-viral agents.

   Key Words   Recombinant DNA, Introduction of DNA into Fungal Cells, Gene Expression Systems, DNA-Protein Interaction, Microbial Physiology, Site-Directed Mutagenesis, Protein Purification and Characterization

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