# Molecular mechanism that suppresses the proliferation of cells with supernumerary centrioles

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $33,544

## Abstract

Project Summary
The long-term goal of our research is to understand the molecular mechanisms that control centriole
biogenesis and how errors in this process contribute to human disease. Centrioles are the structural core of
centrosomes, organelles that nucleate microtubules to build mitotic/meiotic spindles and cilia. During a normal
cell cycle, centrioles duplicate once to ensure their copy number is precisely maintained. The presence of
supernumerary centrioles is a common feature of human tumors and can promote chromosome segregation
errors that are sufficient to drive tumor development in mice. To maintain genome integrity, cells have evolved
a protective centriole surveillance pathway to restrict the proliferation of cells with extra centrioles. The goal of
our application is to unravel the molecular mechanism responsible for ‘sensing’ supernumerary centrioles and
evaluate whether inactivation of this pathway facilitates tumor development in cells with extra centrioles.
Centriole amplification triggers the activation of the PIDDosome, a trimeric protein complex that acts as an
activation platform for Caspase-2. Once activated, Caspase-2 promotes the cleavage of MDM2 and
subsequent stabilization of P53. However, there exists a gap in our understanding of how extra centrioles are
sensed and how this information is relayed to the PIDDosome to trigger P53 activation. To address this
knowledge gap, we developed a genome-wide screening approach to identify genes required to arrest the
growth of non-transformed cells with extra centrioles. Our preliminary data show that distal appendages that
form on mature centrioles are responsible for activating the PIDDosome following centriole amplification. In
Aim 1 of this proposal we will use cell biological, genetic and biochemical approaches to mechanistically
dissect how cells ‘sense’ supernumerary centrioles to trigger PIDDosome activation. In Aim 2, we will
determine the impact of specifically inactivating the centriole surveillance pathway on the proliferation and
oncogenic transformation of cells with extra centrioles in vivo. We are well suited to pursue these studies given
our expertise in studying centriole biology; our development of a unique mouse model to study the impact of
centriole amplification in vivo; and our collaborative relationship with the Regot and Loncarek laboratories, who
are world-experts in high resolution live-cell imaging and correlative light/EM analysis of centriole
ultrastructure. Understanding how normal cells detect centriole amplification addresses a fundamental question
that will provide insight into how aneuploid tumor cells adapt to proliferate robustly with extra centrioles.

## Key facts

- **NIH application ID:** 10054522
- **Project number:** 3R01GM133897-01S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Andrew Jon Holland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,544
- **Award type:** 3
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054522

## Citation

> US National Institutes of Health, RePORTER application 10054522, Molecular mechanism that suppresses the proliferation of cells with supernumerary centrioles (3R01GM133897-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10054522. Licensed CC0.

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