A first-passage-time theory for search and capture of chromosomes by microtubules in mitosis

TL;DR

This paper develops a theoretical model to compute the mean search time of microtubules capturing chromosomes during mitosis, explaining how cells optimize this process to ensure timely cell division.

Contribution

It provides a systematic, rigorous calculation of search times for microtubules with arbitrary kinetics and extends the analysis to multiple targets and nucleating sites, linking theory with experimental data.

Findings

Microtubule kinetics are optimized in yeast and mammals to reduce search time.

In Xenopus, microtubule dynamics are not optimized for search efficiency, indicating additional regulatory mechanisms.

Theoretical estimates align with observed mitotic durations across different cell types.

Abstract

The mitotic spindle is an important intermediate structure in eukaryotic cell division, in which each of a pair of duplicated chromosomes is attached through microtubules to centrosomal bodies located close to the two poles of the dividing cell. Several mechanisms are at work towards the formation of the spindle, one of which is the `capture' of chromosome pairs, held together by kinetochores, by randomly searching microtubules. Although the entire cell cycle can be up to 24 hours long, the mitotic phase typically takes only less than an hour. How does the cell keep the duration of mitosis within this limit? Previous theoretical studies have suggested that the chromosome search and capture is optimized by tuning the microtubule dynamic parameters to minimize the search time. In this paper, we examine this conjecture. We compute the mean search time for a single target by microtubules from a single nucleating site, using a systematic and rigorous theoretical approach, for arbitrary kinetic parameters. The result is extended to multiple targets and nucleating sites by physical arguments. Estimates of mitotic time scales are then obtained for different cells using experimental data. In yeast and mammalian cells, the observed changes in microtubule kinetics between interphase and mitosis are beneficial in reducing the search time. In {\it Xenopus} extracts, by contrast, the opposite effect is observed, in agreement with the current understanding that large cells use additional mechanisms to regulate the duration of the mitotic phase.