Geoffrey Kapler

Biography

DNA replication initiates at specific chromosomal sites termed origins of replication. Whereas regulatory proteins restrict replication to once per cell cycle division, cell cycle control can be overridden during development and tumorigenesis in humans. We are studying a process, termed gene amplification, inTetrahymena thermophila which selectively amplifies the naturally-occurring ribosomal DNA (rDNA) minichromosome 10,000-fold within a single S phase. Using biochemical, molecular, and genetic approaches to identify and characterize cis-acting determinants and trans-acting regulatory proteins, we have uncovered a complex regulatory pathway that involves proteins that compete for binding to the same cis-acting sequence elements. One of these activities, TIF4, appears to be the equivalent of the phylogenetically-conserved yeast origin recognition complex (ORC). Another activity, TIF1, selectively modulates the access of trans-acting replication and transcription activators to disperse determinants that control both processes

Research Interest

Recent experiments also uncovered an amplification-specific cis-acting determinant that might facilitate the selective recruitment ORC to the rDNA replicon during programmed gene amplification