# Initiation of DNA Replication

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $318,241

## Abstract

Summary
Accurate control of genome replication initation is essential for genome stability.
In particular, organisms with multiple replication origins per chromosome must
ensure that initiation of DNA replication at each origin is highly regulated. In
eukaryotes, the cell cycle circuitry controls initiation by a complex series of post-
translation modifications. The manner in which these modifications impinge upon
the function of the replication apparatus is an area of active research and much
remains to be discovered. We have previously shown that archaea of the genus
Sulfolobus possess three replication origins per chromosomes and each fires
once in every cell cycle. In the current proposal we describe a series of
experiments to investigate the control of loading and activation of the conserved
MCM replication helicase. In eukaryotic chromosomes, all replication start sites
are defined by binding of the origin recognition complex, ORC that ultimately
directs the position of loading of the MCM helicase. Given their central role in
replication it is not surprising that components of ORC, such as Orc1, are
essential genes in eukaryotes. Orc1 is evolutionarily conserved in the archaeal
domain of life. The chromosomes of archaea of the genus Sulfolobus contain
three replication origins that are defined by distinct initiator proteins. Furthermore
none of the Sulfolobus Orc1-like initiators are essential for viability. This mosaic
nature of the Sulfolobus chromosome provides a unique tool with which to
dissect the mode of action of the conserved Orc1 proteins in living cells. We will
exploit this tool to perform genetic biochemical and dissections of the role of Orc
in MCM loading in vivo and in vitro. Additionally, our preliminary data reveal the
existence of positive control of the MCM helicase by phosphorylation and we will
determine the basis of this activation of the helicase. In addition to establishing
novel paradigms for prokaryotic DNA replication, our work will serve as a model
for the fundamentally related, yet organizationally more complex, eukaryotic DNA
replication apparatus.

## Key facts

- **NIH application ID:** 10106633
- **Project number:** 5R01GM125579-04
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Stephen David Bell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,241
- **Award type:** 5
- **Project period:** 2018-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106633

## Citation

> US National Institutes of Health, RePORTER application 10106633, Initiation of DNA Replication (5R01GM125579-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10106633. Licensed CC0.

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