Research Interests

The regulation of DNA replication, DNA damage checkpoint in human normal and cancer cells. Identification of target genes, and small molecules for cancer therapy.

Research Program

Maintenance of genome stability is extremely important in the cell cycle, with genomic instability being the hallmark of cancer cells. Cells have evolved multiple mechanisms to prevent genome instability during genome duplication, including DNA damage checkpoint, DNA repair, and regulation of DNA replication. Our research is focused on two fundamental questions about genome stability in human cells. First, how do cells regulate their DNA replication to ensure their genome is duplicated precisely? Specifically, we study how cells prevent premature firing of replication origins to ensure DNA is replicated once and only once per cell cycle. For example, we study the role of geminin- and CDK- dependent pathways in the regulation of DNA replication. Second, we look at how the DNA damage checkpoint is activated in response to intrinsic replication perturbations, as well as extrinsic factors that interfere with DNA replication to generate various DNA damage. Specifically, we focus on the checkpoint activation in cells with DNA re-replication, one type of genome instability. For example, how is the ATR-, Brac1- mediated Fanconi anemia pathway activated in cells with re-replicated DNA? In addition, our lab is interested in translational research. We take advantage of the difference in the regulation of DNA replication between normal cells and cancer cells to identify the target genes and small molecules for cancer therapy. To accomplish this goal, we have established a high throughput screening (HTS) to detect cells with re-replicated DNA in collaboration with NIH Chemical Genomic Center (NCGC). We expect to identify small molecules that selectively induce DNA re-replication and apoptosis in cancer cells via this HTS assay.

Selected Publications

• Zhu W and DePamphilis M. Selective killing of cancer cells by suppression of geminin activity. Cancer Research 69: 4870-4877, 2009.
• Zhu W, Ukomadu C, Senga S, Dhar D., Wohlschlegel J., Kornbluth S. and Dutta A. Mcm10 and And-1/CTF4 recruit DNA polymerase a to chromatin for initiation of DNA Replication. Genes & Development. 21: 2288-2299, 2007.
• Zhu W, and Dutta A. An ATR, BRCA1 mediated FA pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication. Mol. Cell. Biol. 26: 4601-4611, 2006.
• Senga T, Sivaprasal U, Zhu W, Park JH, Arias EE, Walter JC, Dutta, A. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem. 281: 6246-6252, 2005.
• Zhu W, Chen Y and Anindya D. Re-replication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. Mol. Cell. Biol. 24: 7140-7150, 2004.
• Zhu W, Rainville IR, Ding M, Bolus M, Heintz NH, Pederson DS. Evidence that the pre- mRNA splicing factor Clf1p plays a role in DNA replication in Saccharomyces cerevisiae. Genetics 160: 1319-1333, 2002.