Transcriptional regulation and DNA repair mechanism of HSF1-PARP complex by DNA damage stimulation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Yamaguchi University
• Principal Investigator: FUJIMOTO Mitsuaki 山口大学, 大学院医学系研究科, 准教授 (80359900)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: HSF1 / PARP1 / PARP13 / 転写 / DNA修復

Outline of Final Research Achievements

Here, I show that heat shock transcription factor 1 (HSF1) interacts PARP1 through the scaffold protein PARP13. In DNA damage stimulation, inhibition of HSF1-PARP13-PARP1 complex formation caused a redistribution of PARP1 to the DNA damage site and a decrease. Furthermore, this complex formation was required to protect cells from DNA damage stress. Inhibition of complex formation. BRCA1-deficient mammary tumor cells which has a sensitive to PARP inhibitors were inhibited in cell growth formation and tumorigenesis in mice by inhibition of complex formation. These results suggest that HSF1 is involved in the stability of the genomic DNA of cancer cells, and HSF1-PARP complex acts to suppress BRCA1-deficient mammary tumorigenesis.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で、HSF1-PARP13-PARP1複合体がDNAの安定性に関与することを明らかにした。DNAが不安定化するとDNA異常が起こり、この異常が蓄積するとがんが発症する。BRCA1遺伝子の変異で起こる乳がんはDNA修復機構に強く依存することが知られている。マウスを用いた実験から、この複合体の形成阻害がBRCA1変異乳がん細胞の腫瘍形成を顕著に抑制することを明らかにした。よって、HSF1-PARP13-PARP1複合体の解析から、乳がんなどの治療薬の開発に結びつく可能性がある。