Biological complexity: final cell division controls (Introduction)

by David Turell , Thursday, December 09, 2021, 21:35 (861 days ago) @ David Turell

Very precise steps:

https://www.science.org/doi/full/10.1126/science.abm7949

Gulluni et al. report that loss of PIK3C2A inhibits abscission, the final stage of cytokinesis, and triggers lens cell senescence and cataract formation in zebrafish, mice, and humans.

"Individual PI phosphates (PIPs) occur within the inner leaflet of cellular membranes, where they form distinct microdomains that recruit specific proteins and thereby regulate diverse cellular processes... Dynamic remodeling of PIPs is a key regulatory mechanism, and multiple studies confirm the importance of PIP remodeling during cytokinesis, notably in the assembly and constriction of the contractile ring that is required before abscission.

"Inhibition of cytokinesis leads to G1 arrest in the next cell cycle, followed by senescence. Gulluni et al. found that senescent multinucleated cells (resulting from defective cytokinesis) accumulate and intercellular bridges (ICBs), the final membranous connection between two daughter cells, persist in cells from PIK3C2A-null patients. These phenotypes suggest a role for PI3K-C2α in late stages of cell division. Indeed, the authors found that PI3K-C2α localizes to ICBs. Direct binding to both PI(4,5)P2 in the plasma membrane and γ-tubulin restricts PI3K-C2α to the ICB central bulge, a structure called the Flemming body. Furthermore, catalytic activity and proper localization of PI3K-C2α are needed for abscission. Gulluni et al. determined that PI3K-C2α at the ICB uses PI(4)P as a substrate to produce a localized pool of PI(3,4)P2, a lipid not previously known to act in cytokinesis.

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"Recruitment and subsequent release of CHMP4B from the Flemming body must be tightly regulated to ensure that abscission occurs at the correct time and not, for example, while lagging chromosomes persist in the ICB, which would create genomic instability (11). Notably, heterozygous mutations in CHMP4B are linked with early-onset cataracts. However, mice that lack CEP55 develop normally except within the brain. CEP55 is thus not essential for cell division in all cells but is specifically required in neurons, raising the possibility of parallel, cell type–specific pathways to abscission.

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"Differences in cell type– and tissue-specific cell division pathways could also stem from the need to respond to different regulatory pathways. Abscission is thought to be subject to a checkpoint mechanism, delaying the final step of daughter cell separation until all the chromosomes have left the intercellular bridge. Recent findings suggest that activation of abscission is also susceptible to the state of nuclear envelope reassembly and membrane tension across the ICB (9). Could it be that each of these events feeds into a different arm of the abscission pathway? PI3K-C2α has been found to generate PI(3)P in response to shear stress and increased membrane tension (15). By using independent pathways or those with overlapping function, abscission may have evolved to respond to a variety of events to ensure its correct timing and the maintenance of genome stability."

Comment: there is no need to fully understand all the controlling steps. The point is this final step in cell division is extremely tightly controlled by specific molecular steps, which must have been designed for mistake protections, as possible disease results are noted. We learn the underlying steps by noting errors to begin with.