# Structure and Function of DNA Repair Enzymes and Cancer

> **NIH NIH P01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $1,837,238

## Abstract

PROJECT SUMMARY
On a daily basis, each cell in our body is bombarded with some 30,000 endogenous DNA damages per day,
the vast majority of which are repaired by Base Excision Repair (BER). The central hypothesis of this Program
is that, understandably, defects in this BER process drive human carcinogenesis and affect responses to
cancer treatments. The overall goal of this Program Project is to functionally characterize human genetic
variation in the BER enzymes. To accomplish this, we are characterizing potentially damaging germline and
tumor-associated SNPs in the B E R DNA glycosylases, and a number of the downstream enzymes in the
BER pathway, using our strengths in bioinformatics, cell biology, biochemistry, structural biology and single
molecule imaging in order to determine the functions of the wild-type and variant proteins. Our
preliminary data suggest that fundamental mechanistic studies are essential for interpreting human
genetic variation and its influence on cancer etiology and tumor progression. Our program is informed and
driven by the identification and characterization of germline and tumor-associated enzyme variants that
may contribute to the altered DNA repair capacity of human BER enzymes. To realize our goals, variants in
the BER genes are prioritized for study using bioinformatics (Core A) as well as enzymatic activity and
structural information (Project 2). We then test for functional consequences of the variation using a powerful
combination of biological, biochemical, structural, and single-molecule approaches. Core A provides the
bioinformatics underpinning of the Program; Project 1, the biological studies of the human variant proteins in
human cells; Project 2, the structure/function and biochemical analyses of the BER glycosylases; Project 3,
the study of the BER repair process in chromatin; and Project 4, insights into the damage target search
of the wild-type and variant BER proteins. Core B provides purified proteins to Projects 2-4 and cell
cultures of variant clones to Projects 1-4, while Core C provides the administrative support. Taken together,
the mechanistic results obtained by this Program Project provide a unique opportunity to underpin critical
questions surrounding cancer etiology and cancer treatment, thus substantially impacting personalized
medicine.

## Key facts

- **NIH application ID:** 10014581
- **Project number:** 5P01CA098993-14
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Sylvie Doublie
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,837,238
- **Award type:** 5
- **Project period:** 2004-09-03 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014581

## Citation

> US National Institutes of Health, RePORTER application 10014581, Structure and Function of DNA Repair Enzymes and Cancer (5P01CA098993-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10014581. Licensed CC0.

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