Center for
Genomic Integrity

CMSCellular Mechanism Section

Conventional cancer therapies target the characteristics of uncontrolled growth of cancer cells. Due to high level of DNA replication DNA damage compromising or inhibiting DNA replication can trigger cell death. However, cell death is also triggered in healthy tissues, causing dose-limiting side effects. Thus, many efforts are focused on developing cancer therapies that selectively kill cancer cells without adversely affecting healthy tissues. The concept of ‘synthetic lethality’ refers to the cell-lethal effects of the combined inactivation of two genetically distinct pathways. In a cancer setting, synthetic lethality provides a conceptual framework for the development of drugs that are selectively toxic in specific genetic backgrounds associated with tumors. One example is the synthetic lethality of PARP inhibition in tumors carrying mutations in brca1 or brca2. It is likely that other examples of DNA repair-associated synthetic lethal relationships relevant to cancer exist.

We are focusing on small molecules and genome editing strategies that target cancer cells more specifically based on unique genomic features. We will use them as probes to study DNA repair mechanisms and to evaluate their therapeutic potential for cancer treatment.

MBSMolecular Biochemistry Section

We aim to understand the molecular dynamics of DNA replication and repair machineries. Chromosomal DNA replication and repair are essential cellular processes to maintain genetic information from one generation to the next. Eukaryotic DNA replication is a complex process in which many multi-subunit protein complexes participate. Although various kinds of replication factors have been identified, it has been remained largely unknown how those factors work together to faithfully duplicate the chromosome. We investigate the interplay between replication proteins and nucleic acids during DNA synthesis using in vitro reconstitution systems. We especially focus on the regulatory mechanism for the assembly and disassembly of replication/repair machineries on DNA. Our studies will provide a detailed understanding of how replication and repair processes are controlled to maintain genomic integrity.

MGSMolecular Genetics Section

We aim to understand how genomic integrity is maintained at the organism level, especially during development. We use genetically modified mouse and zebrafish as model organisms to study the genetic networks that are important to preserve genomic integrity. We also utilize embryonic stem cells and tissue specific stem cells to study the mechanism of development at the molecular level. Mouse and zebrafish models are complementary to each other. Mice are used as a mammalian model system closely related to human, while zebrafish provide powerful genetics allowing for large-scale genetic and drug screening. Combining these two model organisms and embryonic stem cells that can mimic the developing embryos will strengthen our understanding of genomic integrity in physiological context.