# Structural Investigations Critical to Understanding DNA Damage Recognition and Repair in Cancer

> **NIH NIH R50** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $175,129

## Abstract

SUMMARY
Insuring genomic integrity is fundamental to human health, development as well as the prevention of numerous
disease states including premature aging and cancer. The human genome is under constant threat of damage
through both exogenous (UV Rays, chemicals from cigarette smoke) and endogenous (the oxygen required for
normal cellular respiration) sources. While cellular oxidation-reduction systems exist for detoxifying a number
of the metabolic byproducts, some fraction inevitably escapes to come in contact with the DNA and generate
oxidized lesions that can lead to mutations during replication through free radical damage to bases, strand
breaks and sites of base loss. It is estimated that each cell experiences in excess of 10,000 sites of damage
per day that, if left unrepaired, lead to disease establishment and promote its progression. Understanding the
means by which these sites of damage are recognized and repaired or bypassed is essential to providing
critical information regarding predictive outcomes and therapeutic strategies for cancer patients. This proposal
utilizes structural biology techniques including X-ray crystallography in support of thee NCI-funded programs
aimed at elucidation of the molecular details of key enzymes involved in DNA repair. The focus of project 1 is
the structural and biochemical investigations of DNA glycosylases that recognize and remove oxidative lesions
within the DNA whereas program 2 investigates the mechanisms of replication fidelity of DNA polymerase β,
the repair polymerase responsible for filling nucleotide gaps generated by a glycosylase. Program 3
investigates specialized DNA polymerases, particularly pol θ, and its response to encountering unrepaired
DNA during replication. Pol θ processes DNA double strand breaks in an error-prone manner and upregulation
of the POLQ gene strongly correlates with poor clinical outcome in breast cancer patients. Pol θ has thus
emerged as a compelling drug target for combination therapy of radiosensitization. My role in this proposal will
be to perform structural and biochemical investigations of complexes of polymerases and glycosylases bound
to DNA damage. I will also be characterizing variants of these enzymes identified in cancer patients.
Additionally, I maintain the X-ray equipment and manage the X-ray facility, am responsible for training of new
users and guide students and postdocs in their structural work within these NCI programs. Collectively, this
work is expected to generate important insights into the molecular mechanisms of DNA repair proteins. These
results are expected to have a positive impact because the detailed knowledge of enzyme molecular
mechanisms coupled with studies of cancer variants will increase our understanding of cancer susceptibility
and optimize treatment protocols.

## Key facts

- **NIH application ID:** 10474331
- **Project number:** 5R50CA233185-05
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Brian E. Eckenroth
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $175,129
- **Award type:** 5
- **Project period:** 2018-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474331

## Citation

> US National Institutes of Health, RePORTER application 10474331, Structural Investigations Critical to Understanding DNA Damage Recognition and Repair in Cancer (5R50CA233185-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10474331. Licensed CC0.

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