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Annual Report 2022

Laboratory of Genome Stability Maintenance

Ken-ichi Yoshioka, Rika Matsuo, Yusuke Matsuno, Azusa Takahashi, Haruka Asai, Yuya Manaka, Tarfdel Rafat, Nana Takahashi

Introduction

 Cancer development steps progress through multiple rounds of clonal evolution of cells that have abrogated cancer suppressor genes, such as TP53. Our recent in vitro studies revealed that such clonal evolution is induced with genomic instability, triggered by replication stress-associated DNA double strand breaks (DSBs). A number of chromosomal structural variants (SVs) and single nucleotide variants (SNVs) are usually accumulated in the resulting cells. Supporting this argument, cancer is widely developed with genomic instability. However, while genomic instability is caused with erroneous repair of DNA damages, most cancers with genomic instability are developed without any background mutations in repair systems. This poses a question as to how the massive repair errors are induced.

The Team and What We Do

 Currently ongoing projects are as follows: (1) study of chromatin states that risk genomic instability; (2) analyses of chromatin modifications that are associated with the increased risk of genomic instability; (3) genomic instability risk promoted by UV and γ-ray irradiations; and (4) involvement of genomic instability in antigen presentation. We are pursuing those projects to characterize the regulations risking genomic instability and associated with cancer immunotherapy.

Research Activities

Gamma-ray irradiation and ROS-associated SNV induction

 Genomic instability is induced through erroneous repair of DSBs, in which SVs and SNVs are massively caused. In the analyses in 2022, we observed that γ-ray irradiation dose not directly risk SVs with the DSBs, but indirectly increases the SV risk through the resulting accumulation of replication stress-associated DSBs. We also observed the increase of ROS-associated SBS signature SBS17a and 17b in the resulting cells. While SNV induction is usually correlated with SVs, SNVs increased with the irradiation are not. Together, our results suggest that γ-ray irradiation is associated with the risks of SV induction and ROS-associated SNVs, in which those two risks are separately arisen.

UV exposure and genomic instability

 UV exposure is associated with DNA damages and hence increases cancer risk. However, it is mechanistically unclear how the UV damages are associated with cancer risk. In the analyses in 2022, we observed that UV exposure is associated with the accumulation of replication stress-associated DSBs and hence risking genomic instability. Damages directly caused by UV irradiation are cyclobutene pyrimidine dimer (CPT) and pyrimidine-pyrimidone (6-4) photoproduct (6-4PP). Replication stress-associated DSBs increased when cells undergo to DNA synthesis in the presence of CPT and/or 6-4PP.

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 2022

Journal

1. Suzuki M, Fujimori H, Wakatsuki K, Manaka Y, Asai H, Hyodo M, Matsuno Y, Kusumoto-Matsuo R, Shiroishi M, Yoshioka KI. Genome destabilization-associated phenotypes arising as a consequence of therapeutic treatment are suppressed by Olaparib. PloS one, 18:e0281168, 2023

2. Matsuno Y, Kusumoto-Matsuo R, Manaka Y, Asai H, Yoshioka KI. Echoed induction of nucleotide variants and chromosomal structural variants in cancer cells. Scientific reports, 12:20964, 2022