# Structure-Function Analysis of DNA Replication Initiation Factors Implicated in Disease

> **NIH NIH R35** · STANFORD UNIVERSITY · 2024 · $386,193

## Abstract

PROJECT SUMMARY
 DNA replication is a highly conserved process essential for all life. Since eukaryotic genomes are very
large, they are replicated in parallel from thousands of replication origins. Proper regulation of replication
initiation is essential for maintaining genome stability. Oncogene activation dysregulates replication initiation
and enables rapid cell proliferation in cancer. Key regulators of replication initiation are over-expressed in
cancer, and mutations in these proteins cause rare genetic disorders.
 Yet, the molecular mechanisms that underlie replication initiation remain poorly understood, especially
in multicellular organisms, for two main reasons: (1) replication initiation involves transient protein-protein and
protein-DNA interactions that are very challenging to study using existing biochemical, genetic, and structural
methods; and (2) the most comprehensive studies of replication initiation have been done in yeast, however key
regulators of replication initiation are poorly conserved between yeast and metazoans. Notably, some human
replication factors are 2-3x larger than their yeast counterparts and containing novel domains with unknown
functions.
 My laboratory recently developed a single-molecule imaging platform to visualize replication initiation
in real time. We will use this powerful approach to (i) provide a quantitative description of replication initiation;
(ii) understand how this process changed from yeast to humans; (iii) delineate the role of key replication proteins
and their domains that are unique to metazoans; and (iv) understand why mutations in some replication
initiation factors cause disease. Our work will also provide valuable mechanistic insights into how cancer cells
sustain rapid proliferation by over-activating replication initiation and inform how replication initiation factors
may be used as biomarkers or targets for novel therapies.

## Key facts

- **NIH application ID:** 10929367
- **Project number:** 5R35GM147060-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Gheorghe Chistol
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,193
- **Award type:** 5
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929367

## Citation

> US National Institutes of Health, RePORTER application 10929367, Structure-Function Analysis of DNA Replication Initiation Factors Implicated in Disease (5R35GM147060-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10929367. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*