# Fidelity Mechanisms of DNA Polymerase Beta

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $661,773

## Abstract

PROJECT SUMMARY/ABSTRACT
 Mutations in the human genome give rise to many human diseases including cancer. Mutations are also
beneficial for processes including evolution and adaptive immunity. However, little is known about the
molecular basis of mutagenesis. One mechanism that leads to the introduction of mutations is
misincorporation of nucleotides by DNA polymerases during DNA replication and repair. The focus of our
application is on deoxynucleoside triphosphate (dNTP) substrate selection by DNA polymerase beta (Pol β).
Pol β functions in base excision repair, a process that has evolved to repair oxidative DNA damage. These
types of damage are generated by a cell’s endogenous metabolism as well as exogenous sources such as
ionizing radiation, UV light, and chemotherapeutic agents. During base excision repair, 20,000-50,000
predominantly oxidative DNA lesions are enzymatically removed, leaving small gaps in the DNA that are filled
in by Pol β. Incorrect substrate selection by Pol β during base excision repair has potential to result in genomic
instability. We have recently shown that Pol β also functions in DNA gap filling during microhomology-mediated
end-joining in VDJ recombination, where it plays an important role in generating immune diversity.
 Our broad, long-term objective is to understand how DNA polymerases choose the correct substrate for
incorporation into DNA. Pol β is an excellent model for studying polymerase mechanisms because of its
relatively small size and the ease of purifying protein and growing crystals. The aims of this application are to
understand how Pol β selects the correct dNTP and why it sometimes chooses the incorrect dNTP for
incorporation into DNA. We will employ a powerful combination of biochemical, structural, biophysical,
computational and biological approaches in this multi-investigator project. We will determine how Pol β selects
the correct substrate for incorporation into DNA and how the mechanisms differ for mutator variants of Pol β.
Our research will result in the characterization of the roles of amino acid residues in the selection of substrates
during Pol β catalysis. Our findings will be of fundamental importance in understanding the molecular basis of
substrate selection by Pol β that will likely have broad applicability to other DNA polymerases.

## Key facts

- **NIH application ID:** 10797552
- **Project number:** 1R01CA281044-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Sylvie Doublie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,773
- **Award type:** 1
- **Project period:** 2024-03-07 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797552

## Citation

> US National Institutes of Health, RePORTER application 10797552, Fidelity Mechanisms of DNA Polymerase Beta (1R01CA281044-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10797552. Licensed CC0.

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