Annual Report 2021
Genome Stability Maintenance Unit
Ken-ichi Yoshioka, Rika Matsuo, Azusa Takahashi, Yusuke Matsuno, Mafuka Suzuki, Riko Nakagawa, Haruka Asai, Yuya Manaka, Kakeru Wakatsuki
Introduction
Cancer development steps generally progress through multiple rounds of clonal evolution of cells that have abrogated cancer-suppression systems, such as the ARF/p53 pathway. Based on our recent in vitro model studies, such clonal evolution is triggered by genomic destabilization with the associated mutagenesis. In fact, cancer widely develops through genomic instability that includes inductions of chromosomal structural variants (SVs) and single nucleotide variants (SNVs). However, while genomic instability is mainly caused by erroneous repair of DNA damage, most cancers with genomic instability develop without any background mutations in repair systems. This poses the question of how risk of massive repair errors is increased and regulated.
The Team and What We Do
Currently ongoing projects are as follows: (1) study of chromatin states that risk genomic destabilization; (2) characterization of cellular and chromatin states that are associated with genomic destabilization risk; (3) study of mechanisms that enable suppression of genomic destabilization risk; (4) genomic destabilization risk arising from UV exposure; and (5) studies of abnormalities in human cancer genomes. We are pursuing the first and second projects to identify cancer-risk markers for the innovation of super-early diagnosis methods for cancer, and the third project for the innovation of cancer-prevention drugs and supplements.
Research activities
Correlated inductions of SVs and SNVs
Genomic destabilization that risks cancer development can be caused by DNA double strand breaks (DSBs) arising from replication stress, which induce erroneous repair and hence risk SV induction. The resulting cells usually show a number of SNVs as well as SVs. Such SVs and SNVs are mechanistically caused through distinct pathways (i.e., erroneous DSB repairs and DNA replication errors, respectively), posing the question of whether such SVs and SNVs are separately induced or simultaneously caused during a genomic destabilization process. Here, we observed that SNVs induced in multiple types of human cancer are tightly correlated with SVs, implying correlated SNV induction with SVs. In addition, we also observed the identical correlation in SV and SNV inductions in cells that had undergone clonal evolution in vitro triggered by genomic destabilization. Thus, our results imply that many SNVs in human cancer cells are not induced during canonical replication but are likely caused during DNA synthesis that is associated with the erroneous DSB repair.
Involvement of genomic destabilization in inducing increased resistance to γ-ray irradiation
Our previous studies revealed that cells exposed to γ-ray irradiation accumulate replication stress-associated DSBs and hence transition to a state at higher risk of genomic destabilization. This poses the question of whether in cancer cells that survived radiation therapy, the resulting genomic destabilization is specifically associated with the acquisition of increased resistance. Here, we showed that increased resistance is acquired in the resulting cancer cells that survived multiple rounds of radiation exposure. In addition, this risk is suppressed by simultaneous treatment with PARP inhibitor Olaparib, associated with a repair pathway switch. While homologous recombination (HR) is primarily the major repair pathway of those DSBs, HR is effectively blocked in the presence of Olaparib.
Characterization of cellular states that risk genomic destabilization and identification of compounds that induce effects of genome stability maintenance
Genomic destabilization is generally caused by erroneous repairs. However, although cancers widely develop through genomic instability, most do not show any background mutations in repair systems. This poses questions about the induction of massive repair errors. Here, we found the involvement of a specific chromatin state alteration that is associated with DSB-repair deficiency and hence risk of genomic destabilization. Using the chromatin state as the marker, we further screened compounds that induce a stable chromatin state. Importantly, DSBs accumulated in the cells treated with the screened compounds were effectively repaired, and the resulting clonal evolution was suppressed in association with the effects of genome stability maintenance.
Education
Two graduate students at local universities worked as trainees in our lab and had cancer research training.
Future Prospects
Innovation of drugs (or supplements) that enable cancer prevention through genome stability maintenance.