chTOG is a conserved mitotic error correction factor
Preprint posted on 4 August 2020 https://www.biorxiv.org/content/10.1101/2020.08.03.235325v1
Article now published in eLife at http://dx.doi.org/10.7554/elife.61773
Always have a backup plan: A new mitotic error-correction mechanism mediated by chTOGSelected by Liam Cheeseman
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: 29 September 2020
doi: https://doi.org/10.1242/prelights.24951Read preprint
Also in the cell biology category:
CTCF is essential for proper mitotic spindle structure and anaphase segregation
Actin nucleators safeguard replication forks by limiting nascent strand degradation
BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote replication fork stability and continuous DNA synthesis
preListscell biology category:in the
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
|List by||Sergio Menchero et al.|
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|List by||Nadja Hümpfer et al.|
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
|List by||Osvaldo Contreras|
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
|List by||Alex Eve|
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
|List by||Ana Dorrego-Rivas|
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
|List by||Ana Dorrego-Rivas|
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
|List by||Dey Lab, Samantha Seah|
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
|List by||Yamini Ravichandran|
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
|List by||Maiko Kitaoka et al.|
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
|List by||Paul Gerald L. Sanchez and Stefano Vianello|
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
|List by||Hiral Shah|
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
|List by||Madhuja Samaddar et al.|
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
|List by||Dey Lab|
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
|List by||Sandra Malmgren Hill|
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
|List by||Rob Hynds|
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|List by||Pablo Ranea Robles|
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
|List by||Dey Lab|
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|List by||Sandra Franco Iborra|
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
|List by||Joseph Jose Thottacherry|
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
|List by||Dey Lab, Amanda Haage|