Development of a rational synthetic lethal treatment to eliminate paralog-deficient cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19470
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: Ogiwara Hideaki 国立研究開発法人国立がん研究センター, 研究所, 分野長 (40568953)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: パラログ / 合成致死性

Outline of Final Research Achievements

Synthesic lethality is a phenomenon in which cell death occurs when both genes in a cell are dysfunctional. This phenomenon often occurs between similar genes (paralogs). In cells without one paralog, suppression of the partner's paralog results in synthetic lethality. At this time, a genetic complementary mechanism by which partner mRNA increases at the transcriptional level was known in lower organisms such as mice. In this study, we examined the genetic complementarity mechanism in a human cell model in a paralog knockout cell line. As a result, the phenomenon of complementary paralogs in the partner even if one paralog is missing is thought to be related to quantitative regulation of proteins, rather than transcriptional regulation by genetic complementary mechanisms.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

遺伝学的相補機構は、マウスなどの下等生物で認められた現象であったが、本研究において、ヒト細胞株モデルで検証した結果、パラログ遺伝子間の転写を介した遺伝学的相補機構を確認することができなかった。しかし、当初想定していた転写レベルでの相補機構ではなく、タンパク質レベルでの相補機構が存在する可能性を見出した。これは、これまでに想定されていない細胞内の新規の機構が存在していることを示唆している。