Annual Report 2021
Genome Stress Signaling Unit
Bunsyo Shiotani
Introduction
Cancer is caused by changes to the DNA. Genomic stress, which is caused by environmental, genetic, and DNA replication factors, threaten genomic DNA. When cellular homeostasis is lost due to activation of oncogenes or inactivation of tumor suppressor genes by these genomic stresses, additional genomic stress (DNA replication stress) occurs during DNA replication. DNA replication stress induces DNA replication errors as well as loss, amplification, and translocation of parts of the DNA (acquisition of genomic instability). These can promote cancer development.
The Team and What We Do
Our group are focusing on the DNA replication stress response to elucidate the acquisition of genomic instability due to DNA replication stress resistance and the mechanisms of cancer development and drug resistance, and develop new therapies based on these findings.
Research activities
1) In a lung cancer model, we showed that induction of KRASG12V triggers chromatin compaction and slowing of replication forks, resulting in cell death, and elevated expression of ATR is necessary and sufficient to tolerate KRASG12V-induced replication stress and promote cell malignancy.
2) SMARCA4 deficiency, a SWI/SNF chromatin remodeling complex factor, is associated with high DNA replication stress, which destabilizes DNA replication forks in lung line carcinoma cells and makes them sensitive to ATR inhibitors. Three different ATR inhibitors showed similar results, indicating that SMARCA4 deficiency may be a biomarker of ATR inhibitor efficacy.
3) Analysis of the acquisition of resistance to osimertinib, a molecularly targeted drug that targets EGFR mutations, revealed that abnormal DNA replication promotes acquiring genomic abnormalities that contribute to cancer recurrence.
Education
We provided research guidance to one postdoctoral fellow, and four trainees from Hoshi Pharmaceutical University, Kitasato University, and Keio University.
Future Prospects
Recent genome analysis has reported that genomic abnormalities and mutations accumulate not only in tumor tissues but also in surrounding "apparently normal" tissues. The gradual increase in the number of cells that acquire genetic mutations frequently observed in cancer with aging strongly suggests that the DNA replication stress tolerance mechanism, which is the focus of our research, promotes genome evolution. We aim to elucidate the underlying mechanism of DNA replication stress tolerance and to create novel therapies for cancer cells by utilizing inhibitors of DNA replication stress tolerance regulatory factors.