Annual Report 2024

Laboratory of Genome Stability Maintenance

Ken-ichi Yoshioka, Yusuke Matsuno, Naoki Akiba, Cha Yunjung

Introduction

 Cancer development steps progress thr

 ough multiple rounds of clonal evolution in cells with abrogated cancer suppression systems, such as ARF/p53 pathway. Our in vitro studies revealed that such clonal evolution can be induced by genomic instability, either chromosomal instability (CIN) or microsatellite instability (MSI). In fact, cancer is widely developed with genomic instability. However, while genomic instability could be caused with erroneous repair of DNA damages, most cancers with genomic instability develop without any background mutations in those repair systems, posing a question of how erroneous repair is induced.

The Team and What We Do

 Following projects are currently ongoing: (1) study of chromatin states, i.e., associated with the increased risk of genomic instability; (2) genomic instability risk arisen by UV and γ-ray irradiations; and (3) involvement of genomic instability in tumor neoantigen presentation. We are pursuing those projects to characterize the chromatin state associated with genomic instability risk and genomic instability regulation associated with cancer immunotherapy.

Research Activities

Gamma-ray and UV irradiations and genomic instability

 Genomic instability including structural variant (SV) and single nucleotide variant (SNV) inductions is caused through the erroneous repair of replication stress-associated DSBs, and is often induced by exogenous damages, such as γ-ray and UV irradiations. In 2024, we observed that within two major UV photoproducts, CPDs and 6-4PPs, DNA double strand breaks (DSBs) associated with genomic instability were induced during DNA replication in the presence of CPDs in active genes. These DSBs were induced when CPDs were under the intermediates of transcription coupled-nucleotide excision repair. By contrast, 6-4PPs were associated with cell-cycle arrest; therefore, 6-4PPs were repaired before the entry of S phase and hence not associated with SV and SNV inductions.

Replication stress-associated inductions of MSI and tumor neoantigen

 Microsatellite instability (MSI) arisen under mismatch repair (MMR) deficiency is associated with a better response to immune checkpoint inhibitors. Based on our recent studies, it is suggested that tumor neoantigen can be induced in response to replication stress during MSI induction. In 2024, we performed the screening of MMR inhibitors targeting MSH2, and obtained lead compounds. The chromatin-state alteration under replication stress was suppressed in the presence of the lead compounds even in MMR-proficient cells, which is as usually seen under MMR deficiency.

Education

 One graduate and one undergraduate 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.