Annual Report 2020

Laboratory of Genome Stability Maintenance

Ken-ichi Yoshioka, Yusuke Matsuno, Mafuka Suzuki

Introduction

 Cancer develops through multiple rounds of clonal evolution of cell-abrogated cellular defense systems, such as in the ARF/p53 pathway. Based on our recent studies, such clonal evolution is triggered by genomic destabilization with the associated mutagenesis. However, it is still unclear how genomic destabilization risk increases and how such risk can be regulated.

The Team and What We Do

 We are currently working on the following projects: (1) mechanistic studies of genomic destabilization; (2) co-relation between genomic rearrangements, i.e., SVs and base-substitution mutations, i.e., SNVs; (3) factors increasing the risk of genomic destabilization; (4) cellular and genomic states associated with a higher risk of genomic destabilization; and (5) regulations that lead to genome stability maintenance.

Research activities

Genomic destabilization-associated mutagenesis

 Genomic rearrangements arising during genomic destabilization are generally caused by the erroneous repair of DNA damage. Unlike such genomic rearrangements, base-substitution type mutations were thought to be randomly induced as replication errors. However, our recent results revealed that while mutations induced during replication are limited even in a mismatch repair-deficient background that is associated with higher mutation rates during canonical replication, massive mutations are induced in association with genomic destabilization. In fact, clonal evolution of mutated cells is induced in association with genomic destabilization with the resulting mutagenesis.

Radiation risk

 Exposure to ionizing radiation is associated with cancer risk. It has been thought that such risk elevation is due to the DNA damage caused by the radiation; however, it is still not clear how that damage is further associated with the mutation induction that increases the risk of cancer development. Our results revealed that the primary risk caused by ionizing radiation is the induction of a cellular state at a higher risk of genomic destabilization, which is basically due to the accumulation of replication stress-associated DSBs.

Polyphenols, as genome stabilizers

 Cancer prevention effects are widely shown by the consumption of polyphenols in a number of animal models. Given those cancers usually develop in association with genomic destabilization, one of the possible hypotheses as to the effects induced by the polyphenol might be an effect on genome stability maintenance. We tested this possibility and found that DNA damage having the risk of genomic destabilization is significantly reduced under the treatment of those polyphenols, in which genome stability in the resulting cells is maintained and hence clonal evolution is suppressed.

Education

 Two graduate students in local universities worked as trainees in our lab and had cancer research training.

Future Prospects

 We aim to innovate drugs (or supplements) that enable cancer prevention through genome stability maintenance.

List of papers published in 2020

Journal

1. Matsuno, Y., Atsumi, Y., Alauddin, M., Rana, M.M., Fujimori, H., Hyodo, M., Shimizu, A., Ikuta, T., Tani, H., Torigoe, H., Nakatsu, Y., Tsuzuki, T., Komai, M., Shirakawa, H., and Yoshioka, K. Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability. Scientific Reports, 10 (2020) 5388.

2. Yoshioka, K. and Matsuno, Y. Genomic Destabilization and its Associated Mutagenesis Increase with Senescence-Associated Phenotype Expression. Cancer Science, 112 (2021) 515-522. v