Peter M.J. Burgers, Ph.D.

DEPARTMENT OF Biochemistry & Molecular Biophysics
Keywords: cell cycle, DNA-protein interactions, DNA damage, DNA repair, DNA replication, yeast

Our laboratory is studying nuclear DNA replication and DNA repair in the yeast Saccharomyces cerevisiae. Yeast is an ideal eukaryotic organism to study questions relating to control and mechanism of replication and repair, both at a genetic and at a biochemical level. Current biochemical and genetic efforts focus on the mechanisms which ensures genome fidelity and integrity during DNA replication and the DNA damage response.

Specifically, we aim to understand the functions of the replicative DNA polymerases at the replication fork; the mechanisms by which accessory factors associate with these DNA polymerases to form replication-competent complexes; and how the different replication complexes at the leading strand and at the lagging strand physically interact into a replisome to ensure coordinated DNA replication of the chromosome. Key factors essential for fork progression are also instrumental in coupling DNA replication to the DNA damage response pathways. One of these factors is PCNA, the circular replication clamp that coordinates all of these pathways through its interaction with multiple replication and repair factors.

We are making progress in defining a molecular framework in eukaryotes for (i) damage-induced mutagenesis and for (ii) the DNA damage checkpoint. Damage-induced mutagenesis is initiated by ubiquitination of PCNA. We are studying, by biochemical and genetic means, the pathway of assembly of the "mutasome" coordinated by PCNA, and of factors that control its function. Our studies of the DNA damage checkpoint is targeted to understanding how DNA damage is propagated, via a cascade of DNA binding proteins, a PCNA-like circular clamp and several ATM-like protein kinases, to the cdk kinases that mediates cell cycle progression. It is important to understand these mechanisms in yeast because defects in the highly analogous pathways in humans are known to result in damage susceptibility and cause various forms of cancer.