Research Program: Genetic Mechanisms of Cancer
Associate Professor, Department of Biochemistry, Molecular Biology and Biophysics

bieli003@umn.edu
612-624-2469 — office
612-624-0460 — lab
Preferred method of contact: e-mail

Dr. Bielinksy received her Ph.D. in 1995 from Heinrich-Heine University in Düsseldorf, Germany. She conducted postdoctoral work at Brown University, was a Special Fellow of the Leukemia and Lymphoma Society from 1999-2002 and an American Cancer Society Scholar from 2002-2006. She is currently an associate professor in the Department of Biochemistry, Molecular Biology and Biophysics and a Scholar of the Leukemia and Lymphoma Society.

Research Interests

DNA replication is an integral part of the eukaryotic cell cycle, which coordinates the duplication of the entire genome during S phase and chromosome segregation during mitosis. At the onset of S phase, origins of DNA replication are activated to "fire". Once DNA synthesis has been initiated, the cell is committed to undergo a complete round of division. Deregulation of origin activation results, therefore, in uncontrolled cell proliferation, which is at the heart of diseases such as cancer.

To initiate DNA replication, cells must assemble specific complexes, also called replication forks. Key components of these complexes are the minichromosome maintenance protein 10 (Mcm10) and DNA polymerase-alpha/primase. The latter is the only enzyme in eukaryotic cells capable of synthesizing DNA de novo. This polymerase is thus indispensable for DNA replication. Limiting amounts of it can lead to unstable replication forks and incomplete replication, resulting in chromosome breakage. Therefore, eukaryotic cells have developed a particular mechanism to maintain significant amounts of DNA polymerase-alpha/primase in the nucleus. They stabilize the complex through the interaction with another protein, a nuclear chaperone that is bound to the complex at all times during the cell cycle. This nuclear chaperone is Mcm10. In the absence of Mcm10, the catalytic subunit of DNA polymerase-alpha is degraded in budding yeast and cells lose the ability to replicate their genome. Mcm10 is conserved from yeast to man, and one focus of our laboratory is to understand the regulation of Mcm10.

Another focus in our lab is the investigation of the S phase checkpoint in budding yeast. All eukaryotic cells have evolved various checkpoints to ensure proper cell cycle progression. The S phase checkpoint is activated when replication forks encounter obstacles such as damaged DNA or other impediments that force them to slow down. The S phase checkpoint maintains the stability of replication forks under such circumstances and prevents replication fork collapse, which would also lead to chromosome breakage. S phase checkpoint genes are frequently mutated in cancer cells, and this deficiency might directly contribute to cancer development.

Selected Publications

Das-Bradoo S, Bielinsky AK. Mapping replication initiation sites in eukaryotic genomes. Molecular Methods in DNA Replication (ed., John Walker and Jacob Dalgaard), Humana Press Inc., in press.

Raveendranathan M, Bielinsky AK. Analyzing origin activation patterns by copy-number change experiments. Molecular Methods in DNA Replication (ed., John Walker and Jacob Dalgaard), Humana Press Inc., in press.

Bielinsky AK. Scarce but scary. Nat Genet. 2007;39:707-708 (PDF).

Chattopadhyay S, Bielinsky AK. Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication. Mol Biol Cell 2007;18:4085-4095.

Bolon YT, Bielinsky AK. The spatial arrangement of ORC binding modules determines the functionality of replication origins in budding yeast. Nucleic Acids Res. 2006;34:5069-5080. 

Raveendranathan M, Chattopadhyay S, Bolon Y-T, Haworth JC, Clarke DJ, Bielinsky AK. Genome-wide replication profiles of S phase checkpoint mutants reveal fragile sites in yeast. EMBO J. 2006;25:3627-3639.

Ricke RM, Bielinsky AK. A conserved Hsp10-like domain in Mcm10 is required for the stabilization of DNA polymerase-alpha in budding yeast. J Biol Chem. 2006;281:18414-18425.

Das-Bradoo S, Ricke RM, Bielinsky AK. Interaction between PCNA and di-ubiquitinated Mcm10 is essential for cell growth in budding yeast. Mol Cell Biol. 2006;26:4806-4817.

Bielinsky AK, Raveendranathan M. Encircled: large-scale purification of replication origins from mammalian chromosomes. Mol Cell 2006;21:735-737.

Ricke RM, Bielinsky AK. Mcm10 regulates the stability and chromatin association of DNA polymerase-alpha. Mol Cell 2004;16:173-185.