Annual Report 2023

Laboratory of Genome Stability Maintenance

Ken-ichi Yoshioka, Rika Matsuo, Yusuke Matsuno, Azusa Takahashi, Haruka Asai, Yuya Manaka, Naoki Akiba, Shota Takeda, Touru Aoyama

Introduction

 Cancer development steps progress through multiple rounds of clonal evolution of cells that have abrogated cancer suppression systems, such as mutation induction in 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). In fact, 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 errors of DSB repair are massively 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 and UV irradiations and genomic instability

 Genomic instability is induced through erroneous repair of replication stress-associated DSBs, in which SVs and SNVs are massively caused. In the UV-effect analyses in 2023, we observed that within two major photoproducts, CPDs and 6-4PPs, replication stress-associated DSBs risking genomic instability were induced during DNA replication in the presence of CPDs in active genes. Such DSBs were elevated after 6-4PPs were repaired. This is analogous to the effect of γ-ray, because DSBs risking genomic instability are elevated during DNA replication after DSBs directly arisen by the irradiation were repaired. In the case of UV irradiation, transcription coupled repair of CPDs was associated. Together, our results showed that genomic instability risk arising with UV and γ-ray irradiations are induced in association with the resulting replication stress-associated DSBs.

Association of replication stress for MSI induction and antigen presentation

 Microsatellite instability (MSI) arisen under mismatch repair (MMR) deficiency is associated with a promising response to immune checkpoint inhibitors. Recent studies revealed that MHC class I molecule is expressed in response to replication stress that risks genomic instability. This poses a question whether MMR-deficient cancer cells under replication stress express tumor specific antigen with simultaneously risking MSI induction. In the analyses in 2023, we observed that MHC class I molecule is expressed in response to replication stress regardless of the MMR status. By contrast, repair factors responsible for those DSBs were different: while homologous recombination factor Rad51 was induced in the DSB sites in MMR-proficient cells but not in MMR-deficient cells.

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 that enable cancer therapeutics and prevention through genome stability maintenance.

List of papers published in 2023

Journal

1. Manaka Y, Kusumoto-Matsuo R, Matsuno Y, Asai H, Yoshioka KI. Single base substitution signatures 17a, 17b, and 40 are induced by γ-ray irradiation in association with increased reactive oxidative species. Heliyon, 10:e28044, 2024