SET/TAF1 forms a distance-dependent feedback loop with Aurora B and Bub1 as a tension sensor at centromeres

• Published in: Scientific reports 2020-09, Vol.10 (1), p.15653-15653, Article 15653
• Main Authors: Asai, Yuichiro, Matsumura, Rieko, Hasumi, Yurina, Susumu, Hiroaki, Nagata, Kyosuke, Watanabe, Yoshinori, Terada, Yasuhiko
• Format: Article
• Language: English
• Subjects: 631/80/641/1656; 631/80/641/2002; Aurora Kinase B - metabolism; Biomechanical Phenomena; Centromere - metabolism; DNA-Binding Proteins - metabolism; Enzyme Activation; Feedback, Physiological; HeLa Cells; Histone Acetyltransferases - metabolism; Histone Chaperones - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; Protein-Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); TATA-Binding Protein Associated Factors - metabolism; Transcription Factor TFIID - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-71955-2

During mitosis, spatiotemporal regulation of phosphorylation at the kinetochore is essential for accurate chromosome alignment and proper chromosome segregation. Aurora B kinase phosphorylates kinetochore substrates to correct improper kinetochore-microtubule (KT-MT) attachments, whereas tension across the centromeres inactivates Aurora B kinase, and PP2A phosphatase dephosphorylates the kinetochore proteins to stabilize the attachments. However, the molecular entity of the tension sensing mechanism remains elusive. In a previous report, we showed that centromeric SET/TAF1 on Sgo2 up-regulates Aurora B kinase activity via PP2A inhibition in prometaphase. Here we show that Aurora B and Bub1 at the centromere/kinetochore regulate both kinase activities one another in an inter-kinetochore distance-dependent manner, indicating a positive feedback loop. We further show that the centromeric pool of SET on Sgo2 depends on Bub1 kinase activity, and the centromeric localization of SET decreases in a distance-dependent manner, thereby inactivating Aurora B in metaphase. Consistently, ectopic targeting of SET to the kinetochores during metaphase hyperactivates Aurora B via PP2A inhibition, and thereby rescues the feedback loop. Thus, we propose that SET, Aurora B and Bub1 form a distance-dependent positive feedback loop, which spatiotemporally may act as a tension sensor at centromeres.