# Investigation of human DNA polymerase epsilon variants

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $380,000

## Abstract

SUMMARY
Understanding how cells fail to protect against the mutations and structural rearrangements that are found in
all cancers is critical to ultimately treating the disease. Mutant replication DNA polymerases are found in some
of the most highly mutated tumors known. These tumors also have a very unique mutation spectrum. In our
published work we generated and began to characterize mouse and human cell models of these tumors. While
it was originally thought that this mutagenesis was both necessary and sufficient for tumor development, our
published work and preliminary data strongly implicates additional factors as being necessary for POLE tumor
development.
The main goal of this project is to test our central hypothesis that while POLE tumors are some of the most
highly mutagenic tumors observed, the essential tumorigenic feature of POLE mutants is a failure to stabilize
stalled/collapsed replication forks in response to damaged DNA via inactivation of certain homology-directed
repair genes like BRCA2 and/or loss of a nuclear PTEN activity that both normally stabilize stalled replication
forks and thus suppress genome instability. POLE mutagenesis is concurrently enhanced by promoting
acquisition of mutations in these pathways This hypothesis is based on our published work and unpublished
preliminary evidence. Specifically, this project will 1) Define the mechanistic origins of POLE mutational
signatures; 2) Characterize the cooperation between POLE mutations and homology-directed repair genes, in
particular BRCA2; and 3) Characterize the interactions between a noncanonical PTEN mutant and POLE
mutant alleles.
The proposed work is significant because these studies linking POLE dysfunction to other dysregulated
pathways will provide novel insight into both basic mechanisms of genome instability, but also new possible
therapeutic approaches to treating replication-defective cancers. The work is also significant because it will
advance our understanding of synthetic lethality and neo-epitopes in immune checkpoint therapies. The
proposed work is innovative because 1) it is the first to identify genetic interactions between POLE mutant
alleles and other pathways in tumors and then characterize these interactions in a mammalian system; 2) we
will be the first to examine the effects of these interactions on genome stability and then compare to
sequencing information from large, publicly available cancer genome databases; 3) the proposed studies are
innovative in their use of CRISPR-based genetic engineering of multiple systems (mice, human cells,
organoids) for comparing effects on phenotype and mutagenesis.

## Key facts

- **NIH application ID:** 10367753
- **Project number:** 2R01ES028271-06
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Zachary F Pursell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,000
- **Award type:** 2
- **Project period:** 2017-08-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367753

## Citation

> US National Institutes of Health, RePORTER application 10367753, Investigation of human DNA polymerase epsilon variants (2R01ES028271-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10367753. Licensed CC0.

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