Regulatory mechanisms of attenuating DNA replication stress mediated by a prostate cancer-associated gene SPOP

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07126
• 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: Keio University
• Principal Investigator: Maekawa Masashi 慶應義塾大学, 薬学部(芝共立), 講師 (10771917)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: SPOP / DNA複製 / 脂質代謝 / タンパク質代謝

Outline of Final Research Achievements

This study aimed to elucidate the molecular mechanisms of SPOP (speckle type POZ protein), a substrate recognition receptor for cullin-3 (CUL3) ubiquitin ligase,-mediated prevention of genomic instability. We found that SPOP has a critical role in DNA replication licensing, which is essential for the G1/S phase transition in HaCaT cells. SPOP knockdown inhibited translation of Cdc6 and Cdt1 mRNA, which are required for DNA replication licensing. Our untargeted lipidomics also showed that neutral lipid species were significantly reduced in SPOP-, Cdc6- or Cdt1-knockdown cells, in which DNA replication licensing was inhibited. Our results suggested that SPOP is required for the G1/S transition, and neutral lipid species may be lipid signatures during the phase.

Free Research Field

腫瘍脂質生物学

Academic Significance and Societal Importance of the Research Achievements

前立腺癌は男性の罹患率が急増している癌種であり、高齢化社会を迎えている我が国において、その発症機構を解明し、治療法のレパートリーを拡充することは極めて重要である。SPOP (speckle type POZ protein)は前立腺癌患者の約15%においてアミノ酸変異が見られる前立腺癌関連遺伝子である。そこで本研究ではSPOPの分子機能の詳細に迫った。解析の結果、SPOPが前立腺癌細胞におけるDNA複製ストレス解除に関わるだけでなく、正常な皮膚角化細胞においては、DNA複製の正常な進行 (DNA複製ライセンシング)に必須な遺伝子であることを明らかにした。