BUB1
BUB1 is a conserved serine/threonine mitotic checkpoint kinase that accumulates at unattached kinetochores and supports spindle assembly checkpoint signaling, chromosome alignment, and high-fidelity chromosome segregation[1][2]. Mechanistically, BUB1 promotes checkpoint control by helping recruit core checkpoint proteins to kinetochores and by enabling formation of an APC/C^CDC20^ inhibitory signal when chromosomes fail to attach properly to spindle microtubules[2][3]. BUB1 kinase activity also phosphorylates histone H2A at Thr121, thereby supporting Aurora B localization and attachment-error correction during mitosis[4]. In disease-relevant models, abnormal BUB1 expression associates with chromosome missegregation, aneuploidy, and cancer-related phenotypes, while pan-cancer analysis found BUB1 overexpression in many TCGA tumors and higher expression in clinically aggressive molecular subtypes[4][5]. Compared with the related isoform BUBR1/BUB1B, BUB1 acts more prominently as a kinetochore recruitment and signaling scaffold, whereas BUBR1 is a component of the diffusible APC/C^CDC20^ inhibitor[2][3]. For experimental applications, BAY 1816032 inhibits BUB1 kinase signaling and sensitizes tumor cells toward taxanes, ATR inhibitors, and PARP inhibitors, while BAY-320 inhibits cellular BUB1 activity but shows off-target concerns at required concentrations[6][7].
References:
- [1]. Kim T, et al. Bub1 kinase in the regulation of mitosis. Anim Cells Syst (Seoul). 2021 Feb 17;25(1):1-10. [Content Brief]
- [2]. Vleugel M, et al. Dissecting the roles of human BUB1 in the spindle assembly checkpoint. J Cell Sci. 2015 Aug 15;128(16):2975-82. [Content Brief]
- [3]. Overlack K, et al. A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint. Elife. 2015 Jan 22;4:e05269. [Content Brief]
- [4]. Ricke RM, et al. Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression. J Cell Biol. 2012 Dec 10;199(6):931-49. [Content Brief]
- [5]. Cicirò Y, et al. Expression of the checkpoint kinase BUB1 is a predictor of response to cancer therapies. Sci Rep. 2024 Feb 23;14(1):4461. [Content Brief]
- [6]. Siemeister G, et al. Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo. Clin Cancer Res. 2019 Feb 15;25(4):1404-1414. [Content Brief]
- [7]. Amalina I, et al. Inhibitors of the Bub1 spindle assembly checkpoint kinase: synthesis of BAY-320 and comparison with 2OH-BNPP1. R Soc Open Sci. 2021 Dec 15;8(12):210854. [Content Brief]
