# Mechanisms for recruitment and function of metazoan replication initiation factors

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $321,155

## Abstract

Project Summary
The survival of living organisms depends on the timely and accurate duplication of chromosomal DNA. In all
domains of life, the onset of DNA replication (or initiation) relies on dedicated initiator proteins that bind
genomic sites, termed replication origins, and help load replicative helicases onto DNA. In eukaryotes, the
initiator is the origin recognition complex (ORC), which recruits and deposits the Mcm2-7 helicase motor
module onto DNA to ‘license’ origins. Although core replication initiation factors are conserved across most
eukaryotes and are well-studied in budding yeast, important differences exist with respect to origin recognition
and the regulation of origin licensing between S. cerevisiae and higher eukaryotes. Numerous outstanding
questions therefore remain in the metazoan system regarding origin recruitment and function of core and
accessory DNA replication initiation factors, and the specific contributions of chromatin-associated proteins to
these events. In this proposal, we aim to define at a mechanistic level in metazoan systems how ORC-
dependent DNA remodeling contributes to Mcm2-7 loading, how disease-linked mutations alter initiator
activities, and how ORC-partner proteins promote chromosomal recruitment and function of the initiator, by
integrating biochemical, structural, and cell-based approaches. The findings from this work will have broad
implications for multiple scientific fields, as they will not only help generate models for origin specification,
origin processing, and origin licensing in metazoans, but also contribute to our understanding of DNA- and
chromatin-dependent macromolecular machines. Our studies are also of significant biomedical relevance since
the failure to precisely replicate chromosomal DNA causes genome instability, which in turn underpins many
human diseases, including cancer. In the long-term, the outcomes of our efforts thus have the potential to
provide important starting points for the development of novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10810787
- **Project number:** 5R01GM141313-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Franziska Bleichert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $321,155
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810787

## Citation

> US National Institutes of Health, RePORTER application 10810787, Mechanisms for recruitment and function of metazoan replication initiation factors (5R01GM141313-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10810787. Licensed CC0.

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