A crosstalk between RNA metabolic pathway and DNA damage response involved in the mechanism of cancer growth

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07578
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: WATANABE Kenji 公益財団法人がん研究会, がん研究所 がん生物部, 研究員 (80404333)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: DNA損傷応答 / 転写機構 / がん

Outline of Final Research Achievements

MDC1 accumulates at the site of DNA double-strand break(DSB), which is known to contribute to the early stage of the DNA damage response and repair. It was newly revealed that MDC1 also regulates the splicing complex during normal cell activity,leading to an efficient RNA transcription elongation and splicing.Moreover,MDC1 was involved in de novo RNA synthesis at the DSB, which contributes to facilitating the homologous recombination, an essential pathway for DSB repair. It was also revealed that MDC1-depleted osteosarcoma cell lines exhibit sensitivity to agents that inhibit the transcription of RNA polymerase II. As a result, it was elucidated by this project that the DNA damage response mechanism, the transcriptional control mechanism, and the process of pre-mRNA splicing are efficiently regulated by MDC1.

Free Research Field

DNA損傷応答

Academic Significance and Societal Importance of the Research Achievements

DNA損傷応答反応の初期段階に寄与するMDC1が通常の細胞活動において、一連のRNA転写およびスプライシング反応を恒常的に制御していることを明らかにした。これによりDNA損傷応答機構と転写制御機構やRNA代謝経路が共通の因子であるMDC1によって制御されていることが本課題によって解明された。このことは、これらいずれの経路も活性化し薬剤抵抗性を示すことが知られている“がん幹細胞”を標的としたがんの分子標的治療開発の研究分野において、DNA損傷応答反応とRNA転写機構を標的とした効率的な治療法の開発など一定の波及効果が認めると考えられる。このようにがん研究分野での橋渡し研究が発展すると期待される。