Peter M.J. Burgers, Ph.D.

Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program
Molecular Genetics and Genomics Program
Molecular Cell Biology Program

  • 314-362-3872

  • 314-362-3182

  • 314-362-7183

  • 8231

  • 1911 South Building



  • Cell cycle, DNA damage response, DNA replication, Checkpoints, Mutagenesis, DNA repair, yeast

  • Molecular Biology of DNA replication and damage response in yeast and human

Research Abstract:

Our laboratory is studying DNA replication and DNA damage response mechanisms in the yeast Saccharomyces cerevisiae and in human cells. 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 mechanism which ensure genome fidelity during DNA replication, and on DNA damage response mechanisms that result in cell cycle checkpoint activation and in mutagenesis. 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.

Specifically, we aim to understand the functions of nuclear DNA polymerases at the replication fork under normal replication conditions, and how these functions are altered during replication stress or in response to DNA damage. The plasticity of the DNA replication fork in response to altering conditions and challenges also manifests itself at the level of Okazaki fragment maturation on the lagging strand of the fork. Our biochemical focus is on the machinery that functions during maturation of Okazaki fragments, on protein-protein interactions important for coordinated maturation, and on the iterative hand-off of maturation intermediates between the enzymes that function in the pathway. The presence of [4Fe-4S] clusters in each of the replicative DNA polymerases gives the potential for remarkable regulatory interactions in response to the oxidative environment of the cell.

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 these pathways through its interaction with multiple replication and repair factors. In response to DNA damage, remodeling of the replication fork is mediated through mono-ubiquitination of PCNA. Our biochemical studies are aimed at understanding how ubiquitination alters protein-protein interactions and promotes switching from a normal replication fork to a translesion replication fork. This switch forms the basis for mutagenesis in all eukaryotic organisms. Damage induced mutagenesis is coordinated through the Rev1 protein, that interacts with DNA polymerase ζ and with PCNA, hence the mutasome. In the past, we have identified the pathway that leads to mono-ubiquitination of PCNA and its consequences for recruitment and activity of the mutasome. We are now engaged in delineating other regulatory steps that are required for turning on mutagenesis, and for terminating this response when damage is bypassed. Among these, we are focused on the function of DNA polymerase ζ, which is the major enzyme responsible for the bulk of damage-induced mutagenesis in eukaryotic cells, and on a possible regulatory function of an [Fe-S] cluster present in DNA polymerase ζ.

The DNA damage checkpoint pathway enforces cell cycle arrest to allow timely repair in response to DNA damage and replication stress. We are studying which factors in the cell are responsible for recognizing damage in distinct stages of the cell cycle, and how they start the checkpoint pathway by activation of the kinase activity of Mec1/ATR, the initiating protein kinase in this signal transduction pathway. Our biochemical studies of Mec1/ATR activation are closely interconnected with complementary genetic analyses.

Selected Publications:

Sparks, J.L., and Burgers, P.M. (2015) Error-free and mutagenic processing of topoisomerase 1-provoked damage at genomic ribonucleotides. EMBO J., 34, 1259-1269 PMID: 25777529.

Dovrat, D., Stodola, J.L., Burgers, P.M., and Aharoni, A. (2014) Sequential switching of binding partners on PCNA during in vitro Okazaki fragment maturation. Proc Natl Acad Sci U S A 111, 14118-14123. PMID: 2522876

Kumar, S. and Burgers, P.M. (2013 Lagging strand maturation factor Dna2 is a component of the replication checkpoint initiation machinery. Gen. Dev. 27, 313-321. PMID: 23355394

Sparks, J.L., Chon, H., Cerritelli, S.M., Kunkel, T.A., Johansson, E., Crouch, R.J., and Burgers, P.M. (2012) Rnase H2-Initiated Ribonucleotide Excision Repair. Mol Cell. 47, 980-986.

Makarova, A.V., Stodola, J.L., and Burgers, P.M. (2012) A four-subunit DNA polymerase zeta complex containing Pol delta accessory subunits is essential for PCNA-mediated mutagenesis. Nucl. Acids Res. 40, 11618-11626

Netz, D.J.A, Stith, C.M., Stmpfig, M., Kpf, G., Vogel, D., Genau, H.M., Stodola, J.L., Lill, R., Burgers, P.M.,and Pierik, A.J. (2011) Eukaryotic replicative DNA polymerases require aniron-sulfur cluster for complex formation. Nat. Chem. Biol., 8, 125-132.

Burgers, P.M., Stith, C.M., Yoder, B.L., and Sparks, J.L. (2010) Yeast Exonuclease 5 is Essential for Mitochondrial Genome Maintenance. Mol Cell Biol. 30, 4057-4066.

Burgers, P.M. Polymerase dynamics at the eukaryotic DNA replication fork. (2009) J. Biol. Chem., 284, 4041-4045.

Navadgi-Patil, V., and Burgers, P.M. (2009) The unstructured C-terminal tail of the 9-1-1 clamp subunit Ddc1 activates Mec1/ATR via two distinct mechanisms. Mol. Cell, 36, 743-753.

Last Updated: 8/11/2015 4:54:46 PM

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