# Translesion synthesis DNA polymerases and genome instability

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $337,896

## Abstract

Abstract
This competitive renewal application seeks to investigate the role of translesion synthesis DNA polymerases in
mutagenesis associated with meiotic cell divisions. Unlike somatic mutations that only impact the individual,
DNA changes occurring during meiosis are transmitted to the next generations and lead to the development of
hereditary diseases. With the childbirth age steadily increasing over the past decades, the frequency of de
novo germline mutations in the human population has continuously been on the rise. The resulting hereditary
diseases present a significant burden for the individuals, families and the society, since the patients often
develop multiple medical problems at an early age and require specialized life-long care. The mechanisms
responsible for the generation of germline mutations are poorly understood, as nearly all mechanistic studies of
mutagenesis employ mitotic cells. In the previous cycles of this grant, we discovered and explored a novel
mutagenesis pathway wherein error-prone DNA polymerase ζ (Polζ) is recruited to DNA replication forks
stalled at small hairpin DNA structures and facilitates the bypass of these structures, producing a characteristic
mutational signature. This pathway is silent in healthy mitotic cells because the robust normal replication
machinery is not significantly impeded by the small secondary structures. The Polζ-dependent error-prone
structure bypass, however, becomes a factor when intrinsic or environmental stressors promote fork stalling.
Unexpectedly, our preliminary data suggested that this pathway is also activated during normal meiosis and is
a likely source of recurrent germline mutations in cancer predisposition genes. We will test this hypothesis by
pursuing three Specific Aims. In Aim 1, we will define the contribution of the Polζ-dependent pathway to
germline- and meiosis-specific mutagenesis. In Aim 2, we will use the human POLE gene linked to a hereditary
colorectal cancer predisposition syndrome as a model to identify meiosis-specific hotspots of mutagenesis and
define their relationship to Polζ-dependent hairpin bypass. In Aim 3, we will determine the effects of
environmental DNA damaging agents and replication inhibitors on the accumulation of Polζ-dependent
mutations during gametogenesis. Yeast, mouse and human cell models will be used in these studies, with the
yeast system providing the most power for mechanistic analysis, the mouse providing the opportunity to
experimentally study mutagenesis during mammalian meiosis in vivo, and the data on human samples
establishing the ultimate link to disease. We expect to gain new fundamental knowledge on the mechanism of
mutagenesis in the germline that impacts future generations. We also expect to understand the reasons for
frequent de novo formation of some disease-causing germline variants and the effects of environmental
factors.

## Key facts

- **NIH application ID:** 10428486
- **Project number:** 5R01ES015869-14
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Polina V Shcherbakova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $337,896
- **Award type:** 5
- **Project period:** 2009-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428486

## Citation

> US National Institutes of Health, RePORTER application 10428486, Translesion synthesis DNA polymerases and genome instability (5R01ES015869-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428486. Licensed CC0.

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