Research Projects

Study for mechanistic illustration of genomic destabilization pathways

Most cancers are inevitably developed with genomic instability that can be separated into either chromosomal instability (CIN) or microsatellite instability (MSI) (Yoshioka et al., Cancers 2019). CIN encompasses a wide variety of chromosomal abnormalities including chromosome-number alterations (namely aneuploidy) and chromosomal rearrangements, whereas MSI that is developed under mismatch repair (MMR) deficient background is defined as changes in the lengths of microsatellite fragments that contain short repetitive sequences. As recently illustrated, both are induced owing to the erroneous repair of DSBs arisen by replication stress (Matsuno et al., Nature Com 2019).

Alterations in genomic destabilization risk

Most cancers are developed with genomic instability; paradoxically, however, most of those cancers lack background mutations in DNA repair systems. This raises a question of how genomic destabilization occurs even in normal cells, i.e. the cells with functional DNA repair systems. Here we are studying the cellular states that are associated with genomic destabilization risk and the mechanisms that alter the genomic destabilization risk levels.

Elevation of genomic destabilization risk under radiation exposure

Genomic destabilization risk could be affected by a number of exogenous stressors that include radiation exposure. Our previous studies revealed that DSBs directly caused by radiation are effectively repaired (Atsumi et al., Cell Reports 2015); however, the resulting cells accumulate persisting DSBs arisen in association with replication stress during the following S phase (Minakawa et al., Genes Cells 2016). Based on the accumulating knowledge, genomic destabilization risk arisen by radiation is likely associated with cancer development as well as radio resistance during radiation therapy. We are currently studying the effects on both.

Study for cancer prevention with genome stability maintenance

We are currently studying cancer-prevention effect through the maintenance of genome stability. Cellular states that are associated with higher genomic destabilization risk exhibit senescent cellular phenotypes with accumulating persistent DSBs (Yoshioka et al., Cancers 2019). Intriguingly, cellular phenotypes that are associated with higher risk are largely suppressed when polyphenols are treated (or consumed), under which the effect to maintain genome stability is shown with the resulting cancer-prevention effect (Matsuno et al., Scientific Rep. 2020). Since most cancers are inevitably developed with genomic instability, many cancers are theoretically preventable with this strategy.

Mechanisms to maintain genome stability

The effect to maintain genome stability is induced by the treatment of multiple types of polyphenols; however, the effective point is still not clear. Here we are currently studying the mechanism that leads to genome-stability maintenance when the polyphenols are treated. One of our final goals at this project is to find the way to maximize the effects to maintain genome stability.

Screening of functional drugs (compounds) for genome-stability maintenance

DSBs that are not effectively repairable are accumulated at a time when the genomic destabilization risk is elevated. Monitoring the accumulated DSB levels as one of the markers of such higher risk state, we are currently performing a screening of functional compounds that lead to genome-stability maintenance. The final goal of this project is the innovation of “genome stabilizer” that further enables cancer prevention.

Study of bio-markers that arise in association with genomic destabilization risk for super early diagnosis of cancer

Most cancers are likely induced in association with genomic destabilization. Here, to elucidate cancer risk markers, we are currently studying the effects that arise in association with genomic destabilization and that risks. The final goal of this project is to innovate a super early diagnosis technology of cancer by monitoring genomic destabilization risk.