# The role of Orc6 in DNA replication and cytokinesis.

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $334,125

## Abstract

Abstract.
 The Origin Recognition Complex (ORC), a heteromeric six-subunit protein
complex, is essential for DNA replication. ORC's functions also extend beyond DNA
replication. The smallest of ORC subunits, Orc6 protein, is important for DNA
replication in all eukaryotes. We have shown that in Drosophila Orc6 has an additional
role in cytokinesis through interaction with the septin complex, a highly conserved
polymerizing protein assembly that is critical for cytokinesis in many species and is
recognized as important component of the cytoskeleton. In preliminary studies we
solved the structure of human Orc6 and identified its structural features that contribute
directly to the functions of the protein in replication and cytokinesis. We characterized
the mutations in different domains of Orc6 leading to Meier-Gorlin syndrome (MGS) in
humans, an autosomal recessive disorder characterized by primordial dwarfism and
developmental abnormalities. We showed that despite different underlying molecular
mechanisms these mutations resulted in similar phenotypes, defects in pre-RC
formation and impaired DNA replication. Thus, the diverse molecular functions of Orc6
can be experimentally dissected to obtain a complete understanding of its discrete
roles in the cell. The overall goal of this proposal is to define the distinct mechanisms
of Orc6 function in DNA replication and in cytokinesis using Drosophila as a model
system. We established a humanized Orc6-based Drosophila model system which will
be used to analyze the effects of naturally occurring and structure-guided targeted
mutations of human Orc6 in protein functions. Regulatory insights into replicative and
non-replicative functions of ORC in metazoans are limited, despite decades of
research. Our completion of this project will help to fill this gap in our understanding of
diverse ORC's functions in metazoans and provide clues as to how a specific mutation
or mis-regulation would lead to growth and developmental defects.

## Key facts

- **NIH application ID:** 10296933
- **Project number:** 2R01GM121449-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** IGOR N CHESNOKOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $334,125
- **Award type:** 2
- **Project period:** 2017-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296933

## Citation

> US National Institutes of Health, RePORTER application 10296933, The role of Orc6 in DNA replication and cytokinesis. (2R01GM121449-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296933. Licensed CC0.

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