Research project 1: To study mechanisms and impacts of ecDNAs in cancer cells

Our genomes encode all the information that we require to function. To stably maintain the integrity of our genomes, our cells have evolved elaborate mechanisms to duplicate our genomes accurately, repair any damage to our genomes properly, and segregate a proper number of chromosomes to daughter cells. In cancer cells, genome maintenance systems are often compromised, leading to various types of genomic changes. The increase in gene copy numbers, also known as gene amplification, is a hallmark of cancer cells.

Many people probably envision that gene copy numbers are increased by amplification of a gene on the chromosome. However, an increase in gene copy numbers can also occur extrachromosomally when a gene is circularized outside of the chromosome and that circular DNA is accumulated. Approximately 40% of cancer cells possess large circular DNA, known as Double Minutes or ecDNA, which includes genes such as proto-oncogenes and drug-resistant genes. ecDNAs are believed to be a nuclear factor that has significant impact on the initiation and progression of cancer as well as on acquisition of resistance to chemotherapeutic agents. Although ecDNA was discovered in the 1960s, many questions remain unanswered. Therefore, in my research laboratory, we aim to uncover:

       How are ecDNAs generated and maintained?

       How do ecDNAs impact cellular functions?

Research Project 2: To study mechanisms and impacts of circular DNAs other than ecDNAs

Circular DNAs are not pathological DNAs only seen in cancer cells. For example, budding yeast carries approximately 150 copies of a gene encoding ribosomal RNA (rDNA), which are arranged in tandem on the chromosome. From the rDNA region, circular rDNAs are produced, and its accumulation can accelerate cellular aging. Therefore, we will conduct research to elucidate the mechanisms underlying the production and maintenance of circular rDNAs. Furthermore, a wide variety of other circular DNAs has been observed in normal human cells and other organisms. Thus, we aim to understand the mechanisms by which different circular DNAs are generated and maintained, as well as their functions, with the goal to reveal universalites and specificities behind mechanisms and functions of different circular DNAs.

Research Project 3: To study mechanisms underlying chromosomal gene copy number increase

Gene amplification can occur on the chromosomes. The regions that undergo chromosomal gene amplification in cancer genomes are referred to as Homogenously Staining Regions (HSRs). HSRs are thought to arise from reintegration of ecDNA into the chromosome. However, the mechanism behind this process is not yet fully understood. Additionally, repetitive regions like the rDNA can also undergo rearrangements that increase gene copy number. Therefore, we will understand mechanisms underlying these chromosomal gene copy number increases.