# Structural studies of metazoan origin licensing

> **NIH NIH F31** · YALE UNIVERSITY · 2023 · $47,694

## Abstract

Project Summary
 Developing effective cancer therapies remains a significant challenge due to the heterogeneity of tumor
physiology, cytotoxicity towards non-cancer cells, and the emergence of drug resistance, all of which hamper
positive patient outcome. Thus, there is a critical need for novel anticancer agents with alternate mechanisms
of action. Targeting the DNA replication initiation pathway is an underexplored strategy for cancer therapy.
Origin licensing, the first step of DNA replication initiation during which the replicative helicase Mcm2-7 is
loaded onto replication origins, is of particular interest because its inhibition is selectively cytotoxic towards
cancer cell lines. However, no origin licensing inhibitors have been developed for clinical therapy yet, which is
in part due to an incomplete mechanistic understanding of DNA replication initiation in metazoans. Contrary to
S. cerevisiae, which has been used extensively to study replication initiation both at the biochemical and
structural level, no structures of metazoan origin licensing intermediates containing Mcm2-7 on-pathway to
helicase loading have been solved. How small-molecule origin licensing inhibitors bind and inhibit Mcm2-7
loading factors is likewise unknown. These gaps in knowledge have impeded the development of effective drug
candidates targeting replication initiation. The goal of this proposal is to uncover structural insights into
metazoan origin licensing. A deep understanding of metazoan origin licensing will aid in the
development of small-molecule inhibitors targeting DNA replication initiation complexes and in
defining the mechanisms by which these inhibitors act. These results will contribute to the long-term goal
of developing origin licensing inhibitors as a new class of cancer drugs.

## Key facts

- **NIH application ID:** 10604898
- **Project number:** 1F31CA278331-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Olivia Hunker
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10604898

## Citation

> US National Institutes of Health, RePORTER application 10604898, Structural studies of metazoan origin licensing (1F31CA278331-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10604898. Licensed CC0.

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