# Determining the factors that impact single stranded DNA mutagenesis

> **NIH NIH R35** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $377,500

## Abstract

Abstract
Single stranded DNA (ssDNA) has been demonstrated to by extremely vulnerable to DNA damage. Cancers
often carry long stretches of clustered mutations that likely arose due to damage of ssDNA. While, various
studies have demonstrated that certain mutagens preferentially damage ssDNA, the mechanisms that alter
mutation specificity due to damage in ssDNA and the pathways that prevent mutagenesis at ssDNA are
unknown. The overarching goal of this proposal is to specifically identify the roles of DNA damage checkpoint
proteins, translesion polymerases, ssDNA-specific glycosylases and ssDNA binding proteins in altering the
mutation patterns obtained upon ssDNA-specific damage. My laboratory is in a unique position to advance this
scientific front based on my strong track record in DNA damage and repair, assembled team of collaborators,
and multidisciplinary approach. My expertise in using highly sensitive yeast reporter systems, human cell
culture techniques and the use of bioinformatics tools to probe large data sets and to analyze next generation
sequencing data allow us to develop our research program to understand the pathways modulating ssDNA
mutagenesis in yeast and human cells. Previously, I have demonstrated that alkylating agents and
acetaldehyde have an ssDNA-specific mutation signature in yeast and in cancers. These mutation signatures
provide us with a highly sensitive tool to determine how changes in various DNA repair, damage bypass and
damage sensing pathways alter mutagenesis by ssDNA-specific mutagens. Here, we propose to determine 1)
How cell cycle dependent translesion polymerase expression alters mutation signatures in ssDNA; 2) The role
of ssDNA binding Replication Protein A complex in protecting ssDNA from exogenous damage; 3) The role of
DNA damage checkpoint activation in modulating the mutation signatures associated with ssDNA damage; 4)
Which DNA glycosylases function on ssDNA and alter the mutation signatures due to ssDNA damage; and 5)
What are the mutagenic outcomes when translesion polymerases are unable to bypass ssDNA damage. This
set of research projects will address a key gap in knowledge in understanding the mechanisms that alter the
hypermutability of ssDNA in cells. Our work will enable us to identify and develop better cancer preventative
measures for individuals who are prone to increased genome instability and ssDNA formation in their cells.

## Key facts

- **NIH application ID:** 10892851
- **Project number:** 5R35GM151021-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Natalie Saini
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,500
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892851

## Citation

> US National Institutes of Health, RePORTER application 10892851, Determining the factors that impact single stranded DNA mutagenesis (5R35GM151021-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10892851. Licensed CC0.

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