# Centrosome biogenesis and copy number control

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $24,284

## Abstract

Summary of the funded grant R01GM114119-07:
The long-term goal of our lab is to understand the molecular mechanisms that control centriole duplication and
ensure the accurate distribution of the genome during cell division. Centrioles form the core of centrosomes,
which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic
spindle. Centrioles can also be modified to form basal bodies, which template the formation of cilia and play
central roles in cellular signaling, fluid movement, and locomotion. To coordinate these diverse cellular
processes, centriole copy number must be precisely controlled. Cells begin G1 phase with two centrioles,
which are duplicated during S/G2 phase and are then carefully partitioned into both daughter cells during
mitosis. We and others have shown that extra centrioles cause cell division errors that are sufficient to drive
malignant transformation. Understanding the mechanism by which cells achieve the once per cycle duplication
of the centrioles is, therefore, an important fundamental question of considerable relevance to human health.
Although significant progress has been made in understanding the composition of centrioles, it remains unclear
which specific steps in centriole formation are controlled by the enzymatic regulator Polo-like-kinase 4 (PLK4).
Equally unclear is how a critical regulatory step, termed the ‘centriole-to-centrosome conversion’ (CCC),
functions to maintain centriole homeostasis by enabling new centrioles to acquire competence for duplication.
Our proposed research seeks to capitalize on our identification of key interactions and contributors to centriole
formation to elucidate molecular mechanisms that control centriole assembly. We will examine three
independent components of centriole biogenesis control: the translational regulation of PLK4 expression, the
impact of PLK4 phosphorylation of specific substrates in centriole assembly, and the function of a new
component required for the CCC. Aim 1 will define how a pair of conserved upstream open reading frames in
the PLK4 mRNA regulate critical aspects of PLK4 expression. Aim 2 will mechanistically dissect how a critical
PLK4 phosphorylation site we identified on STIL controls centriole assembly. Finally, Aim 3 will define how a
new centriole protein, PPP1R35, functions to promote the CCC. Understanding how centriole assembly is
regulated will reveal fundamental principles of organelle homeostasis and provide insight into the molecular
basis of human diseases caused by centriole dysfunction.

## Key facts

- **NIH application ID:** 10447474
- **Project number:** 3R01GM114119-07S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Andrew Jon Holland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $24,284
- **Award type:** 3
- **Project period:** 2015-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447474

## Citation

> US National Institutes of Health, RePORTER application 10447474, Centrosome biogenesis and copy number control (3R01GM114119-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10447474. Licensed CC0.

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