Eibes Susana, Lakshmi R Bhagya, Rajendraprasad Girish, Weinert Brian T, Kamounah Fadhil S, Gamon Luke F, Rodriguez-Calado Sergi, Meldal Morten, Davies Michael J, Pittelkow Michael, Choudhary Chunaram, Barisic Marin
Cell Division and Cytoskeleton, Danish Cancer Institute, Copenhagen, Denmark.
Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
EMBO J. 2025 May 27. doi: 10.1038/s44318-025-00469-2.
Parthenolide is a natural compound that has shown highly promising anticancer activity. Even though its mode of action has been studied for decades, its antimitotic activity has been largely overlooked, limiting the understanding of its full anticancer potential. In this study, we combined click-chemistry with quantitative mass spectrometry and cell biology to elucidate the mechanism of action of parthenolide in mitosis. We show that parthenolide does not act as a microtubule-targeting agent in cells. Instead, it binds to the kinetochore protein ZNF207/BUGZ, preventing the establishment of proper kinetochore-microtubule attachment. Our results show that parthenolide covalently binds to Cys54 of BUGZ via Michael addition to its α-methylene-γ-lactone moiety. Since Cys54 is located within the second zinc-finger domain of the BUGZ microtubule-targeting region, we propose that parthenolide interferes with the microtubule-binding ability of BUGZ, consequently preventing kinetochore-microtubule attachments required for accurate chromosome congression to the spindle equator.
小白菊内酯是一种天然化合物，已显示出极具前景的抗癌活性。尽管其作用方式已被研究了数十年，但其抗有丝分裂活性在很大程度上被忽视了，这限制了对其全部抗癌潜力的理解。在本研究中，我们将点击化学与定量质谱和细胞生物学相结合，以阐明小白菊内酯在有丝分裂中的作用机制。我们发现小白菊内酯在细胞中并非作为微管靶向剂起作用。相反，它与动粒蛋白ZNF207/BUGZ结合，阻止正确的动粒 - 微管附着的建立。我们的结果表明，小白菊内酯通过对其α-亚甲基-γ-内酯部分进行迈克尔加成，与BUGZ的Cys54共价结合。由于Cys54位于BUGZ微管靶向区域的第二个锌指结构域内，我们推测小白菊内酯会干扰BUGZ的微管结合能力，从而阻止染色体精确汇聚到纺锤体赤道所需的动粒 - 微管附着。
