# The Huwe1 ubiquitin ligase regulates mitosis, genomic stability and oncogenesis.

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $370,575

## Abstract

Abstract
Progression from a non-transformed normal cell to a malignant cancer cell requires multiple genetic changes
that activate oncogenes while restraining tumor suppressors. This occurs via the acquisition of genetic mutations
and changes of gene copy number. Whole chromosome and segmental aneuploidy can alter copy number of
relevant oncogenes and tumor suppressors and perturbation of the machinery controlling the fidelity of chromo-
some segregation during mitosis is sufficient to promote tumor development via the generation of aneuploidy.
The HECT-domain ubiquitin ligase HUWE1 coordinates the proteasomal-mediated degradation of proteins with
crucial roles in cell division, differentiation and survival and recent work has shown that inactivation of HUWE1
contributes to tumor development. Initially, we generated and studied conditional knockout mice in which HUWE1
inactivation was targeted to the nervous system. We used this mouse model to characterize the role of HUWE1
in neurogenesis. We found that the activation of MYCN oncoprotein and MYCN-dependent transcriptional net-
works are crucial events operating downstream of HUWE1 and whose de-regulation leads to developmental
aberrations in the HUWE1-null brain. We also determined that genetic and epigenetic mechanisms drive loss-
of-function alterations of HUWE1 in a significant fraction of human brain tumors. More recently, our work has
revealed novel and unexpected functions of HUWE1 that have defined this ubiquitin ligase as crucial regulator
of mitotic fidelity whereby loss of HUWE1 induces chromosome mis-segregation and an unstable genome. The
present proposal embodies three Specific Aims that will investigate the novel functions of HUWE1 and will serve
as entry point into the tumor suppressive mechanisms of HUWE1. In Aim 1 we will investigate the events that
are controlled by HUWE1 to preserve mitotic fidelity and genome integrity. Aim 2 will examine the role of candi-
date HUWE1 substrates that we have identified through unbiased proteomic methods for the accumulation the
mitotic phenotype initiated by loss of HUWE1 activity. In Aim 3 we will proceed to address the full scope of
genetic lesions that cooperate with the accumulation of DNA damage and the mitotic phenotype triggered by
HUWE1 deletion to initiate brain carcinogenesis using the Sleeping Beauty transposase insertional mutagenesis.

## Key facts

- **NIH application ID:** 9938516
- **Project number:** 5R01CA239698-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Antonio Iavarone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938516

## Citation

> US National Institutes of Health, RePORTER application 9938516, The Huwe1 ubiquitin ligase regulates mitosis, genomic stability and oncogenesis. (5R01CA239698-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938516. Licensed CC0.

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