DBBS

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.

Burgers, PM. Polymerase dynamics at the eukaryotic DNA replication fork. J Biol Chem 2009 284: 4041-4045.
 
Navadgi-Patil VM, and Burgers PM. Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. J Biol Chem 2009 283: 35853-35859.
 
Nick McElhinny SA, Gordenin DA, Stith CM, Burgers PM, and Kunkel TA. Division of labor at the eukaryotic replication fork. Mol Cell 2008 30: 137-144.
 
Wood A, Garg P, and Burgers PM. A ubiquitin-binding motif in the translesion DNA polymerase Rev1 mediates its essential functional interaction with ubiquitinated proliferating cell nuclear antigen in response to DNA damage. J Biol Chem 2007 282: 20256-20263.
 
Majka J, Niedziela-Majka A, and Burgers PM. The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. Mol Cell 2006 24: 891-901.