Annual Report 2022
Laboratory of Genome Stress Signaling
Bunsyo Shiotani
Introduction
Genomic stress is caused by environmental, genetic, and DNA replication factors. These genomic stresses cause DNA replication stress during DNA replication. DNA replication stress causes genomic instability, promoting cancer development.
The Team and What We Do
Our group is focusing on the DNA replication stress response and cellular response to tolerate DNA replication stress, as well as the associated mechanisms of cancer development and acquisition of drug resistance. Based on these mechanisms, new cancer prevention and cancer treatment methods will be developed.
Research Activities
1) We revealed the mechanism by which normal cells exhibit DNA replication stress tolerance by regulating ATR kinase-dependent PrimPol-dependent repriming in response to KRAS mutations in the early stages of carcinogenesis, and the resulting acquisition of genomic abnormalities.
2) We showed that SMARCA4 deficient lung adenocarcinoma cells are highly sensitive to ATR inhibitor due to destabilization of DNA replication fork by high DNA replication stress and that DNA replication stress is further increased when combined with a PARP inhibitor, enhancing the effect of the ATR inhibitor.
3) We found that DNA replication stress occurs when EGFR mutation cells are treated with Osimertinib, a molecularly targeted drug. DNA replication stress tolerance is involved in this process and that inhibitors of DNA replication stress tolerance may suppress the Osimertinib resistance.
4) Phosphoproteomic analysis in response to DNA replication stress identified a factor that regulates DNA replication velocity. This factor negatively regulates replication speed in a phosphorylation-dependent manner and contributes to genome stability.
Education
We provided research guidance to one postdoctoral fellow, and 6 trainees from Hoshi University, Kitasato University, Tokyo Medical and Dental University, and Keio University.
Future Prospects
DNA replication stress tolerance is a driving force for genome instability during cancer development and malignant transformation, such as acquisition of metastatic potential and drug resistance. We aim to elucidate the mechanism by which DNA replication stress tolerance promotes genomic instability and carcinogenesis, and to create new preventive methods and cancer therapies by inhibiting DNA replication stress tolerance control factors.