# Regulation of genomic stability by ORC

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $300,435

## Abstract

Maintenance of genomic integrity is paramount to cell survival. Precise duplication of our genome and
appropriate cellular response to genotoxic stress is critical to maintain genome stability. Origin
Recognition Complex (ORC, composed of six subunits) and ORC-Associated (ORCA) are required for
the initiation of DNA replication and regulate heterochromatin organization. Multiple subcomplexes of
ORC and/or individual ORC subunits regulate different aspects of cell cycle progression and thus play
pivotal roles in the maintenance of genomic stability. The long-term goal of my laboratory is to
understand how ORC executes and coordinates various aspects of cell growth, proliferation and
survival. The smallest subunit of ORC, Orc6, is required for DNA replication and also coordinates
cytokinesis. The scientific premise of this proposal that human Orc6 is required for DNA replication
progression and DNA Damage Response is based on strong preliminary data. We have exciting
preliminary data demonstrating yet another novel role of Orc6, in DDR. We observe that the levels of
Orc6 increase upon DNA damage and that Orc6 undergoes specific phosphorylation during oxidative
DNA damage. Further, cells lacking Orc6 fail to activate ATR upon DNA damage. The objective of the
present proposal is to answer fundamental questions on the roles of Orc6 in regulating S-phase and
during DDR. Our hypothesis, based on preliminary data, is that Orc6 interacts with replication fork
components and facilitates DNA replication and upon DNA damage the loss of this interaction inhibits
replication fork progression. With our expertise and experience in cell biological and biochemical
characterization of Orc6 and strong preliminary data, we are ideally positioned to pursue the following
specific aims: 1) Determine the role of Orc6 in replication fork progression. 2) Determine the role of Orc6
in DNA damage response. 3) Determine the role of post-translational modifications on Orc6 in DDR and
cell cycle progression. An important question in the field that has remained to be answered is why do
ORC proteins remain bound to chromatin in postG1 cells? This proposal is significant because we
address this question by studying how Orc6 regulates replication fork progression and it evaluates for
the first time the role of preRC proteins in DNA damage response. This proposal is conceptually
innovative because we will rigorously dissect novel regulatory mechanisms of Orc6 in DNA replication
progression and DNA damage response. This proposal is technologically innovative because it employs
state of the art cell biological techniques, including super-resolution imaging combined with biochemical
and single molecule biophysical approaches. Understanding how Orc6 governs multiple pathways
including DNA replication, mitosis and DDR is expected to uncover novel pathways that would be useful
to prevent tumorigenesis and key to allow more effective therapeutic targeting to combat cancer.

## Key facts

- **NIH application ID:** 9947974
- **Project number:** 5R01GM125196-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Supriya G Prasanth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,435
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947974

## Citation

> US National Institutes of Health, RePORTER application 9947974, Regulation of genomic stability by ORC (5R01GM125196-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9947974. Licensed CC0.

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