# Spindle Assembly Checkpoint Silencing

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $454,118

## Abstract

PROJECT SUMMARY
Eukaryotic cell cycle is tightly controlled by an intricate sequence of events where both gene expression and
protein degradation are under intense regulation. When the cell cycle is dysregulated, uncontrolled division
ensues–a hallmark of cancer. Therefore, cell cycle checkpoints, such as the spindle assembly checkpoint
(SAC), ensure faithful chromosome segregation and produce healthy daughter cells. During an active
checkpoint, transcription is reduced and the primary ubiquitin ligase of mitosis, the Anaphase-Promoting
Complex/Cyclosome (APC/C), is inhibited by the 4-subunit Mitotic Checkpoint Complex (MCC). Once the
chromosomes are ready and the checkpoint is satisfied, the APC/C is freed from MCC inhibition through
conformational rearrangements that permit MCC ubiquitination. The APC/C targets several well-established
cell cycle regulators (e.g., Cyclin B and Securin) and chromatin regulators, including the chromatin building
blocks–nucleosomes, for destruction, coupling mitotic exit and transcription. The APC/C-dependent
progression through mitosis is incredibly complicated as it requires the participation of dozens of proteins,
including activators, inhibitors, kinases, AAA-ATPases, and substrates. How all this regulation is successfully
integrated on a single APC/C scaffold is unclear but highly significant because it is at the intersection of both
protein degradation and gene expression for G1 phase. By reconstituting these processes in vitro with
innovative techniques, such as time-resolved cryo-EM and mass photometry, we can better understand how
polyubiquitination occurs, how specific cell cycle effectors influence the conformational states of MCC-bound
APC/C, and how the nucleosome is targeted by the APC/C. The information gained from these studies will lead
to an unprecedented understanding of the SAC and coordinated gene expression, which is at the heart of
development, cell biology, and countless disease processes, including cancer.

## Key facts

- **NIH application ID:** 10919756
- **Project number:** 5R35GM128855-07
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Nicholas Gene Brown
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $454,118
- **Award type:** 5
- **Project period:** 2018-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919756

## Citation

> US National Institutes of Health, RePORTER application 10919756, Spindle Assembly Checkpoint Silencing (5R35GM128855-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10919756. Licensed CC0.

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