α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity
| Autor: | Helder Maiato, Joana T. Lima, Claudia Guasch Boldú, Jorge G Ferreira, Carolina Lemos, António J. Pereira, Bernardo Orr, Marin Barisic, Girish Rajendraprasad, Luísa T. Ferreira |
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| Rok vydání: | 2020 |
| Předmět: |
Tubulin—tyrosine ligase
Centromere Kinesins Mitosis Biology Microtubules Article Kinetochore microtubule 03 medical and health sciences 0302 clinical medicine Microtubule Tubulin Detyrosination Chromosome instability Cell Line Tumor Humans Cytoskeleton 030304 developmental biology 0303 health sciences Kinetochore Cell Biology Cell biology biology.protein 030217 neurology & neurosurgery Cell Cycle and Division |
| Zdroj: | Journal of Cell Biology The Journal of Cell Biology Ferreira, L T, Orr, B, Rajendraprasad, G, Pereira, A J, Lemos, C, Lima, J T, Guasch Boldú, C, Ferreira, J G, Barisic, M & Maiato, H 2020, ' α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity ', The Journal of Cell Biology, vol. 219, no. 4, e201910064 . https://doi.org/10.1083/jcb.201910064 |
| ISSN: | 0021-9525 |
| DOI: | 10.1083/jcb.201910064 |
| Popis: | Detyrosination is a frequent posttranslational modification of long-lived microtubules that inhibits microtubule depolymerase activity in vitro. Ferreira et al. combine manipulation of tubulin tyrosine ligase and carboxypeptidase (Vasohibins-SVBP) activities with state-of-the-art microscopy in human cells to show that α-tubulin detyrosination allows centromeric MCAK to discriminate between correct and incorrect kinetochore–microtubule attachments and ensure mitotic fidelity. Incorrect kinetochore–microtubule attachments during mitosis can lead to chromosomal instability, a hallmark of human cancers. Mitotic error correction relies on the kinesin-13 MCAK, a microtubule depolymerase whose activity in vitro is suppressed by α-tubulin detyrosination—a posttranslational modification enriched on long-lived microtubules. However, whether and how MCAK activity required for mitotic error correction is regulated by α-tubulin detyrosination remains unknown. Here we found that detyrosinated α-tubulin accumulates on correct, more stable, kinetochore–microtubule attachments. Experimental manipulation of tubulin tyrosine ligase (TTL) or carboxypeptidase (Vasohibins-SVBP) activities to constitutively increase α-tubulin detyrosination near kinetochores compromised efficient error correction, without affecting overall kinetochore microtubule stability. Rescue experiments indicate that MCAK centromeric activity was required and sufficient to correct the mitotic errors caused by excessive α-tubulin detyrosination independently of its global impact on microtubule dynamics. Thus, microtubules are not just passive elements during mitotic error correction, and the extent of α-tubulin detyrosination allows centromeric MCAK to discriminate correct vs. incorrect kinetochore–microtubule attachments, thereby promoting mitotic fidelity. Graphical Abstract |
| Databáze: | OpenAIRE |
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