# Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $537,971

## Abstract

Tumor cells make mutations, creating genetic variants that adapt to stressful environments. The
majority of cancer driver mutations may be caused by replication errors, but the sources and
mechanisms of such replication errors in human tumors are poorly understood. This critical gap
in knowledge hinders our ability to effectively manage cancer. The human genome is
characterized by DNA sequence complexity and high repetitive DNA content, but we lack
detailed mechanisms as to how this complex genome is replicated, limiting our understanding of
the endogenous processes that promote cancer development. DNA polymerases encounter
many Difficult-To-Replicate Sequences, or DiToRS, within repetitive regions that cause
replication fork stalling. If not navigated efficiently, DiToRS lead to double strand breaks and
genome instability. Our long-term goals are to illuminate mechanisms of human genome
replication and expand knowledge of replication errors in tumor evolution. This project will
discover how human cells carry out essential synthesis of DiToRS genome-wide, and the
genetic consequences of incomplete DiToRS replication. Our established interdisciplinary team
has unique expertise in studying DiToRS regions of the human genome, and has made
important mechanistic advances towards understanding DiToRS replication. Our recent studies
implicate DNA polymerases eta (Pol η) and kappa (κ) as being essential for this process, and
advance a new paradigm in which Pols η and κ have adopted critical functions for complex
genome replication. Because these polymerases have low fidelity, we hypothesize that by
requiring cells to engage Pols η/κ in DiToRS replication, replication stress increases replication
errors in tumor cells. To test this innovative hypothesis, we will use human cell models and a
physiologic source of replication stress linked to oncogene activation: dNTP substrate depletion.
Aim 1 will study DNA polymerase biochemistry and identify key replication proteins required for
DiToRS replication. Aim 2 will investigate the critical Pol η functions required to promote tumor
cell survival in the presence of replication stress, and the impact of Pol η on ATR/Chk1 inhibitor
targeted therapies. Aim 3 will measure mutations arising in non-tumorigenic and tumorigenic
cells under stress, and develop new computational tools to interrogate cancer genomes for
replication errors. Our mechanistic studies will provide key insights into the mechanisms by
which oncogene activation results in replication errors that drive tumorigenesis, and reveal new
biomarkers of tumor progression. Insights into mutational mechanisms gained from this project
can be leveraged in precision oncology approaches to cancer therapy.

## Key facts

- **NIH application ID:** 10134271
- **Project number:** 5R01CA237153-03
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Kristin A Eckert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,971
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134271

## Citation

> US National Institutes of Health, RePORTER application 10134271, Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions (5R01CA237153-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134271. Licensed CC0.

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