# Mutational spectra of bulky DNA lesions

> **NIH NIH R01** · UNIVERSITY OF RHODE ISLAND · 2022 · $360,125

## Abstract

Many environmental toxins damage DNA and cause diseases. The exposure of cells with DNA damaging agents
results in the formation of a host of different DNA lesions, a subset of which can give rise to mutations. If one
were to plot the frequency and type of mutation as a function of the position along a gene, a distribution is
generated that is commonly referred to as a mutational spectrum. Mutational spectra are usually happened by
sites at which mutagenic events occur more frequently than expected. These are mutational hotspots and the
formation of hotspots can arise from three scenarios: formation, repair and replication. It is reasonable to
speculate that these events are modulated by the local sequence environment surrounding the base to be
modified, or the DNA lesion to be repaired or replicated. It is important for environmental scientists to provide
insights into the evolutionary changes that foreshadow tumor development before overt clinical symptoms
appear. This goal is crucial because some diseases, such as tumors, show few clinical symptoms until the
disease has reached a late, usually fatal stage. Early onset genomic biomarkers might enable intervention to
eliminate or curtail development of the disease. The biomarkers of a disease caused by a specific toxin can be
obtained by studying the mutational spectra of DNA lesions generated from the toxin. Experimental studies of
the mutations and mutation spectra induced by environmental toxins have traditionally focused on single
mutations. However, the origins of mutational hotspots is complicated by the neighboring contexts. The selective
formation, replication, and repair of a DNA lesion can, in principle, be influenced by the surrounding nucleotide
environment from both 5’ and 3’ ends. A nearest-neighbor analysis of a certain DNA lesion (NXN, X = lesion, N
= one of the four nucleotides) will provide a structural rationale for mutational spectra in environmental toxin
related human tumors. In this proposal, we will study individual lesions of environmental toxins under all the
genetic and epigenetic relevant contexts. In this project, we select two important environmental toxins, 4-amino
biphenyl (ABP) and amino alpha carboline (AaC) to study the mutational spectra of their major DNA lesions and
correlate with mutational signatures of diseases caused by them. The central hypothesis of this project is that
DNA lesions generated by environmental toxins will cause different mutational spectra in a sequence dependent
manner. The Specific Aims are: Specific Aim 1: Chemical synthesis and identification of bulky DNA adduct
containing oligonucleotides. Specific Aim 2: Mutational spectra of bulky lesions in cell. Specific Aim 3:
Replication bypass of lesions by translesion synthesis polymerases. At the conclusion of this project we will
have demonstrated how the interaction between environmental toxins and mutational spectra. These studies
shall utilize in a combination of genetic, chemical, and ...

## Key facts

- **NIH application ID:** 10312790
- **Project number:** 5R01ES028865-05
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Deyu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,125
- **Award type:** 5
- **Project period:** 2018-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312790

## Citation

> US National Institutes of Health, RePORTER application 10312790, Mutational spectra of bulky DNA lesions (5R01ES028865-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312790. Licensed CC0.

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