# The APOBEC in APOBEC mutagenesis

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2020 · $31,457

## Abstract

THE APOBEC IN APOBEC MUTAGENESIS
ABSTRACT
 Mutations drive the initiation and progression of cancer. The leading druggable source of mutation in
cancer, cytosine deamination by a subset of the nine-membered APOBEC family of DNA deaminase enzymes,
leaves a distinct mutation signature on the cancer genome. This signature is characterized as C-to-T and C-to-
G mutations in a TCA/T trinucleotide context, and thus APOBEC-dependent mutations can be resolved
computationally from other processes of mutation in clinical next-generation tumor sequencing datasets. While
specific APOBEC3 (A3) enzymes have been implicated as the main progenitors of this mutation signature
(namely, A3B, A3H, and A3A), the literature is full of conflicting data and it is not clear which of these enzymes
contributes the most and whether other A3 enzymes may also contribute. I propose to resolve this debate
through two specific aims. First, I will develop an A3-null haploid cell model system in order to systematically
assay the genomic impact of individual APOBEC family members and document enzyme-specific mutation
signatures. Second, I will use CRISPR to create individual A3 knockout clones in APOBEC signature-positive
cell lines to understand how individual A3 enzymes contribute to functional resistance mutations and clonal
evolution. In addition, I will use both of these wet lab experimental data sets to inform computational pipelines
to reconstruct the APOBEC signature in publicly available tumor sequencing datasets. Collectively, I anticipate
that these experiments will determine the APOBEC enzyme (or enzymes) responsible for mutagenizing cancer
genomes across numerous cancer types. In turn, this fundamental knowledge is expected to inform the
development of future diagnostics and therapies to prevent this mutational process and poor clinical outcomes
including drug resistance and metastasis.

## Key facts

- **NIH application ID:** 9967794
- **Project number:** 5F31CA243306-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Matthew C Jarvis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,457
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967794

## Citation

> US National Institutes of Health, RePORTER application 9967794, The APOBEC in APOBEC mutagenesis (5F31CA243306-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9967794. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*