# Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development.

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2021 · $349,988

## Abstract

Abstract
 APOBEC family cytidine deaminases are prominent mutators of cancer genomes, often causing
thousands of C to T base substitutions in affected tumors. These enzymes normally function within the
immune system and lipid metabolism. How APOBECs become dysregulated and the role subsequent of
APOBEC-induced genetic instability has in promoting cancer progression are unclear. Also unknown is
whether APOBECs induce other types of genetic instability in tumors in addition to base substitutions caused
by deamination. The overall objective of this proposal is to identify mechanisms that enable APOBEC
mutagenesis, determine how this activity alters cancer genomes, and assess the contribution of this genetic
instability to carcinogenesis. Aim 1 will determine if increased levels of single strand DNA caused by chemical
and oncogene-induced replication stress facilitates APOBEC mutagenesis. We will measure the effects of
replication stress on APOBEC-induced mutation frequencies in human cells, determine if cancer cells
displaying endogenous APOBEC activity also display markers of replication stress, and determine whether
replication stress induced by Her2 activation synergizes with APOBEC mutagenesis to alter cell proliferation
and accelerate tumorigenesis in a mouse model. Aim 2 will address how deficiencies in chromatin modifiers
influence APOBEC mutagenesis. We have determined that loss of chromatin modifying enzymes, which are
also frequently inactivated during cancer development, increase the frequency of APOBEC-induced mutations
in yeast. The mechanisms underlying this effect will be determined and re-capitulated in human cells.
Additionally, associations between chromatin modifier loss and elevated numbers of APOBEC-induced
mutations in sequenced cancers will be bioinformatically evaluated. Aim 3 will investigate whether APOBECs
are capable of inducing chromosomal rearrangements during cancer development. We will measure
APOBEC-induced frequencies of non-allelic recombination and copy number variation in yeast and human
cells as well as evaluate whether APOBECs mutagenize the single strand DNA intermediates formed during
these recombination events to cause kataegis. The results from the experiments proposed in these Aims will
likely demonstrate that mutation-driven, cancer-associated changes in DNA metabolism increase APOBEC-
induced mutagenesis, investigate an expanded role for APOBECs in promotion of additional types of genetic
alterations, and directly characterize the ability of APOBEC-generated mutagenesis to promote tumorigenesis.
Successful completion of these aims will describe a critical aspect in the development and progression of a
significant number of human tumors.

## Key facts

- **NIH application ID:** 10150813
- **Project number:** 5R01CA218112-05
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** STEVEN A ROBERTS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,988
- **Award type:** 5
- **Project period:** 2017-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150813

## Citation

> US National Institutes of Health, RePORTER application 10150813, Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development. (5R01CA218112-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150813. Licensed CC0.

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