# Cell Cycle Control of the Cytoskeleton

> **NIH NIH R37** · DANA-FARBER CANCER INST · 2020 · $347,100

## Abstract

This proposal addresses the mechanisms controlling microtubule length, the size and function of the
anaphase spindle, and the coordination of anaphase spindle function with other key cellular events during
mitotic exit. Because the spindle is a self-organizing structure, the regulation of microtubule length is a major
mechanism controlling overall spindle size. Spindle size is controlled globally by the concentration or activity
of factors that promote microtubule growth or disassembly. Additionally, “measuring” mechanisms that
mediate length-dependent microtubule assembly or disassembly have also been described. The best-
studied length-dependent mechanism occurs through the activity of the kinesin-8 family of microtubule
motors. Compromised kinesin 8 function in mammalian cells leads to high frequencies of chromosome
missegregation and and the formation of abnormal nuclear structures, which are common in cancer, called
micronuclei. We recently showed that micronuclei can cause “chromothripsis”, a major mutational process
leading to chromosome rearrangement in cancer.
 In the last funding period, we defined the mechanism by which a yeast kinesin 8 selectively trims longer
microtubules. In contrast to previous proposals, a combination of biochemical and single molecule imaging
experiments lead to a new conformational switch model, involving kinesin 8 recognition of bent tubulin at the
microtubule end, triggering microtubule disassembly. Building on a new high resolution cryo-EM structure
and other data, we now propose to test this model and work out the molecular mechanism for bent tubulin
recognition. Additionally, in the last funding period we have made a significant advance in understanding
how anaphase spindle function is coordinated with the reassembly of the nuclear envelope around
chromosomes to form daughter cell nuclei. We found that spindle microtubules block the recruitment of
nuclear envelope (NE) containing nucleoporins to decondensing chromosomes, but allow other aspects of
NE assembly to occur. This leads to irreversibly defective NE assembly on lagging chromosomes,
explaining why the NE around micronuclei undergoes spontaneous disruption, a key step in generating
chromothripsis. These findings alter the thinking on the organization of mitotic exit in metazoan cells.
Rather than precise checkpoint controls, our findings indicate that chromosome segregation and NE
assembly are only loosely coordinated through the timing of anaphase spindle disassembly. The absence of
precise regulatory controls can explain why errors during mitotic exit are frequent, and represent a major
source of catastrophic genome rearrangements. A series of cell biological experiments is proposed to
address key unanswered questions, such as the mechanism by which microtubules inhibit NPC assembly. A
tractable system using the fission yeast S. japonicus is described that will enable us to use powerful genetic
tools for understanding NE assembly and its coordinat...

## Key facts

- **NIH application ID:** 9980909
- **Project number:** 5R37GM061345-19
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DAVID S PELLMAN
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,100
- **Award type:** 5
- **Project period:** 2000-07-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980909

## Citation

> US National Institutes of Health, RePORTER application 9980909, Cell Cycle Control of the Cytoskeleton (5R37GM061345-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980909. Licensed CC0.

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