# Mechanisms of Genome Stability

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $375,365

## Abstract

Precise duplication of our genome and appropriate cellular response to genotoxic stress is critical to
maintaining genome stability. Origin Recognition Complex (ORC, composed of six subunits) and ORC-
Associated (ORCA) are required to initiate 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. In the last two decades, my (and my group’s)
research effort has been instrumental in understanding how these multitalented ORC proteins govern origin-
independent roles during the cell cycle. The long-term goal of my laboratory is to understand how ORC
executes and coordinates various aspects of cell growth, proliferation and survival. With our expertise and
experience in cell biological and biochemical characterization of ORC and strong preliminary data, we are
ideally positioned to pursue the following two projects: 1) The role of the smallest subunit of ORC, Orc6, in
replication progression and mismatch repair (MMR) 2) The role of pre RC factors in regulating DNA
damage response (DDR) and chromatin organization during G1. The smallest and the most enigmatic
ORC protein, human Orc6 is required for DNA replication and also coordinates cytokinesis. Our recent work
has shown the dispensability of human Orc6 in DNA replication licensing and identified an unexpected role for
human Orc6, which is to promote S-phase progression post pre-RC assembly and in MMR. The scientific
premise of program projects is based on data from our lab that ORC is required for licensing-independent roles
in DNA damage response. Our experiments are critical to establishing the new paradigm emerging ‘is human
Orc6 a component of ORC?’ We propose that hOrc6 plays a fundamental role in genome surveillance during
S-phase. The objective of project 1 is to answer fundamental questions on the biochemical roles of Orc6 in
regulating S-phase and during MMR. Our unpublished work shows that the largest subunit of human ORC,
hOrc1, shows robust accumulation at sites of laser-induced DNA damage. Orc1 is an AAA+ ATPase,
possesses a BAH domain, and binds to chromatin by associating with various post-translationally modified
histones. The objective of project 2 is to understand the fundamental molecular mechanisms of ORC in DDR
and chromatin organization, using Orc1 as a tool, we probe into the coordination of these processes. This
proposal is conceptually innovative because we will rigorously dissect novel regulatory mechanisms of ORC
function in DDR and chromatin organization. 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 ORC governs multiple pathways, including DNA
replication, mitosis, and DDR is expected to uncover novel path...

## Key facts

- **NIH application ID:** 10772342
- **Project number:** 1R35GM152450-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Supriya G Prasanth
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,365
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772342

## Citation

> US National Institutes of Health, RePORTER application 10772342, Mechanisms of Genome Stability (1R35GM152450-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10772342. Licensed CC0.

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