Abstract
BackgroundAsymmetric cell division, whereby a parent cell generates two sibling cells with unequal content and thereby distinct fates, is central to cell differentiation, organism development and ageing. Unequal partitioning of the macromolecular content of the parent cell — which includes proteins, DNA, RNA, large proteinaceous assemblies and organelles — can be achieved by both passive (e.g. diffusion, localized retention sites) and active (e.g. motor-driven transport) processes operating in the presence of external polarity cues, internal asymmetries, spontaneous symmetry breaking, or stochastic effects. However, the quantitative contribution of different processes to the partitioning of macromolecular content is difficult to evaluate.ResultsHere we developed an analytical model that allows rapid quantitative assessment of partitioning as a function of various parameters in the budding yeast Saccharomyces cerevisiae. This model exposes quantitative degeneracies among the physical parameters that govern macromolecular partitioning, and reveals regions of the solution space where diffusion is sufficient to drive asymmetric partitioning and regions where asymmetric partitioning can only be achieved through additional processes such as motor-driven transport. Application of the model to different macromolecular assemblies suggests that partitioning of protein aggregates and episomes, but not prions, is diffusion-limited in yeast, consistent with previous reports.ConclusionsIn contrast to computationally intensive stochastic simulations of particular scenarios, our analytical model provides an efficient and comprehensive overview of partitioning as a function of global and macromolecule-specific parameters. Identification of quantitative degeneracies among these parameters highlights the importance of their careful measurement for a given macromolecular species in order to understand the dominant processes responsible for its observed partitioning.
Highlights
Asymmetric cell division, whereby a parent cell generates two sibling cells with unequal content and thereby distinct fates, is central to cell differentiation, organism development and ageing
Bidirectional mother-bud transfer assuming a static geometry According to the “narrow escape” approximation, the escape of particles with diffusion constant D from a spherical volume V through a narrow circular opening of diameter d can be asymptotically described by an exponential decay with a mean escape time of: te where Ke corresponds to the first-order rate constant for escape [29,30,31,32]
The parameters can be categorized into two groups: parameters that globally influence the partitioning of any molecular content (d,T,Vm,σ) and content-specific parameters (Dm,Db,φm,φb)
Summary
Asymmetric cell division, whereby a parent cell generates two sibling cells with unequal content and thereby distinct fates, is central to cell differentiation, organism development and ageing. Protein granules can be composed of metabolic enzymes, protein degradation machinery or misfolded/damaged proteins in complex with chaperones [7,8,9,10] Some of these assemblies exist constitutively, whereas others form in response to changes in the environment. The nucleus contains extrachromosomal circular DNA (episomes), of which the extrachromosomal ribosomal DNA circles (ERCs), formed via recombination in the rDNA locus, are a prominent example. Some of these large macromolecular assemblies, namely aggregates of misfolded/damaged proteins and episomes, are largely excluded from the bud during yeast cell division [11,12,13]. The mechanisms responsible for asymmetric partitioning of protein aggregates and episomes are a subject of ongoing discussion
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