Molecular mechanisms by which chromosomes regulate mitotic cell division and its relevance to causing human diseases

2023 Fiscal Year Final Research Report

• Project/Area Number: 16K21749
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Research Field: Cell biology
• Research Institution: Ibaraki National College of Technology (2018, 2020-2023); ID Pharma (2019)
• Principal Investigator: Yokoyama Hideki 茨城工業高等専門学校, 国際創造工学科, 准教授 (60397908)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: 細胞骨格・運動 / 分裂期 / 紡錘体 / 染色体分配 / 疾患誘導機序

Outline of Final Research Achievements

RECQL4 is mutated in Rothmund Thomson syndrome, characterized by cancer susceptibility. We find RECQL4 is a microtubule-associated protein (MAP) required for chromosome alignment to the metaphase plate. We detect that the patient cells, lacking RECQL4 protein, show chromosome misalignment, proposing that the chromosome misalignment may be the cause of the disease. We also find VPS72, one of the chromatin-remodeling complex proteins, is essential for postmitotic nuclear re-assembly. Mechanistically, VPS72 binds to postmitotic chromatin and incorporate a histone variant H2AZ on chromatin that enables to assemble compact and functional nuclei. SART1 is previously shown to be important for pre-mRNA splicing and mitotic progression, but the mitotic role of SART1 have not been characterized in detail. We identify SART1 is also a MAP localizing uniquely to spindle poles. We show SART1 mechanistically recruits pericentriolar material proteins and contributes to spindle pole assembly.

Free Research Field

細胞生物学、生化学

Academic Significance and Societal Importance of the Research Achievements

ロスムンド・トムソン症候群の原因タンパク質RECQL4の新たな機能と、疾患の誘導メカニズムを提案することができた。また細胞分裂などの過程に比べて十分に研究されていない核の再形成に、VPS72依存的なH2AZの取り込みが重要であることを解明できた。さらにSART1のこれまでに例のない局在の仕方（SART1キャップ）と紡錘体極の成熟での機能を発見。これらの時期・場所特異的な機能はin vitroやヒト培養細胞に加えて、カエル卵抽出液を使った再構成系を用いたからこそ得られた成果である。今後これらの知見や研究ツールを用いて、研究分野また当研究室でのさらなる研究の展開が期待できる。