Novel pathway for DNA double-strand break repair associated with tyrosyl-DNA phosphodiesterase

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K19974
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: Hiroshima University
• Principal Investigator: Tsuda Masataka 広島大学, 統合生命科学研究科(理), 助教 (00734104)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: DNA二本鎖切断 / 放射線類似作用物質

Outline of Final Research Achievements

The present study reveals a synergistic sensitivity of cells depleted for tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 to radiomimetic drugs. These findings raise the possibility that TDP1 and TDP2 inhibitors could selectively target tumors with perturbed TDP2 and TDP1 expression, respectively. In fact, the homozygous deep deletion of the TDP2 gene was seen in 0.4% and 0.8% of 818 breast-invasive carcinomas and 333 prostate cancer patients, respectively. Based on this finding, the administration of a radiomimetic drug in TDP2-deficient cancer cells in combination with TDP1 inhibitors may also provide a new anti-cancer strategy to target a specific class of tumors. Target inhibition of TDP1 or TDP2 is an attractive tool for cancer therapy, since gene knockout experiments with mouse and human cells show that TDP1 or TDP2 is not essential for organismal survival.

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

ブレオマイシンなどの放射線類似作用物質はがん治療に使われている。新規DSB修復経路でTDP1やTDP2が欠損している患者がいれば、ブレオマイシンタイプの抗がん剤が有効な治療薬となる可能性がある。TDP2遺伝子がホモ接合型に欠損している乳がんや前立腺がんが見つかっている。このがん細胞に放射線類似作用物質とTDP1阻害剤を投与すれば、標的のがん細胞のみを特異的に殺傷できると推定される。