chTOG is a conserved mitotic error correction factor
Preprint posted on August 04, 2020 https://www.biorxiv.org/content/10.1101/2020.08.03.235325v1
When a cell assembles a mitotic spindle, chromosomes attach to the spindle microtubules via their kinetochores. Once fully assembled, the spindle will generate tension on bioriented chromosomes, which will signal that anaphase may take place. However at the start of cell division, these attachments are somewhat random, and incorrect kinetochore attachments may form. These attachments are usually under low tension, which can be detected by the cell. Several mechanisms exist to destabilise and correct these erroneous attachments: the most well-known one is an Aurora B kinase-mediated mechanism, which phosphorylates substrates on low-tension kinetochores, destabilising the attachment and leading to their release from the spindle.
In this preprint by Jacob Herman and colleagues, the authors identify a new intrinsic mechanism by which the cell detects and rectifies incorrect kinetochore attachments, which is independent of the Aurora B pathway. Colonic and hepatic tumour overexpressed gene (chTOG) is a protein that is essential for microtubule dynamics and spindle formation. Previously, the authors have shown that the yeast homologue of chTOG, called Stu2, is able to sense tension on kinetochores and selectively stabilise correct attachments, or destabilise incorrect attachments . Here, the authors show that this mechanism is conserved in human chTOG, and forms a novel error correction pathway that does not require phosphorylation by Aurora B kinase. They further identify a specific chTOG mutant which behaves in a wild-type manner in terms of regulation of microtubule dynamics and spindle assembly, but does not display any error-correction function. In cells expressing this mutant, incorrectly attached kinetochores persisted, and contained more microtubules per kinetochore than in cells expressing WT chTOG. In summary, this study presents evidence of a previously unknown error correction pathway in human cells.
- chTOG localises to kinetochores independently of microtubules in human cells: chTOG still localised to kinetochores of cells treated with nocodazole to depolymerise all microtubules.
- Two conserved residues in the basic patch of chTOG are essential for cell viability: mutation of two highly conserved lysines did not affect spindle formation or microtubule dynamics, but reduced cell viability and prevented chromosome alignment.
- The two lysine residues are essential for a novel error-correction function of chTOG: following STLC washout, WT chTOG cells aligned their chromosomes, whereas the mutant chTOG cells did not. The kinetochores in these cells were attached to more microtubules than in WT cells, suggesting that WT chTOG can correct erroneous attachments by destabilising microtubules, but the mutant cannot.
- This error correction pathway is independent of Aurora B kinase, and intrinsic to the kinetochore: following washout from STLC, Aurora B inhibition in cells expressing mutant chTOG had a cumulative effect, preventing chromosome alignment, suggesting the pathways are independent. Furthermore, depletion of chTOG also had no effect on the phosphorylation status of Hec1, an established Aurora B substrate.
What I liked about this work:
During my PhD, I worked with chTOG and know how tricky it can be to study, as both its depletion and overexpression have a number of pleiotropic effects, and result in catastrophic phenotypes in mitotic cells. The discovery of a novel function for chTOG that is independent from its functions in spindle assembly and regulation of cytoskeletal dynamics is therefore an impressive achievement. The elucidation of a novel error-correction pathway that is intrinsic to the kinetochore in human cells is also very exciting, and raises a lot of questions for future research.
There is some ambiguity regarding the mutant chTOG’s inability to align chromosomes following STLC washout. Are the defects seen only caused by the persistence of incorrectly attached kinetochores, or could there be an additional defect in chromosome congression? The authors find an Aurora B-independent error correction pathway. Are these two pathways redundant, or do they respond to different cues? If so, what are these cues? Several studies have shown that chTOG (or its homologues) has both microtubule polymerase and depolymerase activities. Does this error-correction function take place via its depolymerase activity, or does chTOG require other microtubule-destabilising proteins?
 Miller, M.P., Asbury, C.L. & Biggins, S. A TOG Protein Confers Tension Sensitivity to Kinetochore-Microtubule Attachments. Cell 165, 1428-1439 (2016).
Posted on: 29th September 2020Read preprint
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