# Role of DNA structural dynamics in mutagenesis and oncogenesis

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $371,095

## Abstract

Project Summary
Mutations drive evolution, account for genetic variants in the population, and are the primary cause of
cancer and other genetic disorders. Yet our molecular understanding of the biochemical processes that
cause mutations remains rudimentary. For most mutational processes, we do not understand why the
mutational probabilities vary by many orders of magnitude depending on the type of base substitution and
sequence context. Most mutational patterns cannot be explained by the 1D sequence or 3D structural
characteristics of the DNA motif in which they are found. While mutational processes due to exogenous
sources (e.g. UV, smoking) have been described extensively, studies increasingly point to DNA replicative
errors as an important and potentially dominant source of disease-causing mutations. However, the
molecular mechanisms that underlie DNA replicative errors and their contributions to oncogenesis are not
fully understood. In addition, over half of the mutational processes identified in human cancers have
unknown biochemical origins. The main hypothesis in this proposal is that DNA dynamics that alter the
mode of base pairing is a major driver of mutational processes. The project will experimentally characterize
sequence and mismatch-dependent DNA base pair dynamics with unprecedented breadth and depth, and
generate conformational propensities describing the sequence-specific probabilities of forming alternative
mutagenic conformations. This knowledge will be used to develop a predictive understanding of replication
errors generated by human polymerase ε, one of two polymerases tasked with eukaryotic nuclear DNA
replication. The critical and necessary technological innovation is the development of breakthrough
techniques for measuring DNA structural dynamics in high throughput, enabling studies of over hundreds
and in some cases thousands of sequence variants. Aim 1 will determine the propensities for various
mismatches to form Watson-Crick like conformations, measure the signatures of replicative error for
proofreading deficient human polymerase ε, and advance a predictive model for sequence- and mismatch-
dependent nucleotide misincorporation. Aim 2 will determine the propensities to sample unpaired
conformations, measure the signatures of replicative error for proofreading proficient human polymerase ε,
and advance a predictive model for sequence- and mismatch-dependent replicative errors. Aim 3 will
determine propensities to form Hoogsteen base pairs, and uncover mutational processes driven by
Hoogsteen-mediated damage. By developing a deep and predictive understanding of DNA replication
infidelity and damage, this work will help illuminate fundamental processes that drive evolution and
oncogenesis while also providing a conceptual framework and experimental tools that can help catalyze the
discovery and characterization of other mutagenic and biochemical processes driven by DNA dynamics.

## Key facts

- **NIH application ID:** 10124402
- **Project number:** 5R01GM089846-11
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Hashim M Al-Hashimi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,095
- **Award type:** 5
- **Project period:** 2010-09-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124402

## Citation

> US National Institutes of Health, RePORTER application 10124402, Role of DNA structural dynamics in mutagenesis and oncogenesis (5R01GM089846-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10124402. Licensed CC0.

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