# Mechanisms of Genome Integrity

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $551,971

## Abstract

PROJECT SUMMARY
Our chromosomes are constantly bombarded with a variety of insults, resulting in damage that
must be repaired. Cells have evolved mechanisms to detect and repair broken strands of DNA,
thereby preventing loss of important genetic information. Double‐stranded DNA breaks (DSBs)
are a type of damage that lead to particularly disastrous outcomes. If not corrected, DSBs can
cause gross chromosomal rearrangements, which are the hallmark of all forms of cancer.
 Homologous recombination (HR) is a conserved pathway that cells can use to repair DSBs,
and HR is necessary to prevent and repair the damage that arises during DNA replication. When
a DSB occurs, the DNA ends are processed to generate 3' single‐strand DNA (ssDNA) overhangs.
The ssDNA ends then pair with homologous sequence elsewhere in the genome, and the missing
DNA is replaced using the homologous DNA as a template for replication. Finally, the replicated
intermediate is resolved, regenerating the continuity of the broken DNA. HR requires the
coordinated action of a complex repertoire of proteins, which are responsible for sensing damage,
recruiting essential factors, and processing and repairing the damaged DNA. The consequences
of disrupting HR are devastating. For example, mutations in the RAD51 recombinase are
embryonic lethal in mice, and mutations in human RAD51 are linked to breast cancers. In
addition, defects in BRCA2 account for at least 5% of all breast cancers and also confer a genetic
predisposition to ovarian cancer. BRCA2 is thought to help regulate HR, and loss of this
regulation may be the reason why this gene is linked to hereditary cancers. New discoveries will
be necessary to fully understand the mechanistic basis for these outcomes.
 Our research program is focused on understanding how proteins sense and respond to
damaged DNA and they then repair the damaged DNA to prevent mutations that can lead to
cancer. To help address these problems we have developed unique technologies that allow us to
directly visualize hundreds of individual molecules using optical microscopy, which enables us
to monitor the spatial and temporal progression of DNA repair and DNA replication in real‐time
at the single‐molecule level. Using this approach, we seek to define the fundamental mechanisms
that our cells use to replicate and repair DNA, with the long‐term goal of understanding how
errors during these processes can lead to chromosomal rearrangements.

## Key facts

- **NIH application ID:** 10375574
- **Project number:** 5R35GM118026-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Eric C Greene
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $551,971
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375574

## Citation

> US National Institutes of Health, RePORTER application 10375574, Mechanisms of Genome Integrity (5R35GM118026-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375574. Licensed CC0.

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