# Fork Restart at Replication Barriers and Effects on Genome Stability

> **NIH NIH R01** · TUFTS UNIVERSITY MEDFORD · 2020 · $306,393

## Abstract

PROJECT SUMMARY
Replication of the genome is a fundamental process necessary for life. During the replication of
the millions of DNA base-pairs that make up a genome, the replication fork encounters barriers
that must be overcome, including DNA structures, strongly bound proteins, or damaged or
cross-linked bases. After the barrier is resolved or bypassed, the replication fork must restart as
accurately as possible to avoid chromosome breakage; one mechanism by which this happens
involves proteins that are normally used for a process called homologous recombination, which
occurs by DNA strand invasion. Recently, it has been recognized that this process may be
regulated by nuclear location, with the stalled replication fork relocating to the nuclear periphery
to undergo restart. The long-term objective of this application is to understand the process of
fork restart, its regulation by nuclear location, and its role in preventing genome instability and
deleterious chromosome breaks. The specific aims are (1) to elucidate the role of nuclear pore
localization in fork restart and regulation of recombination, and (2) to investigate the effect of
fork restart on repeat instability. We have shown that expanded CAG repeat sequences, which
form DNA structures, are particularly reliant on fork restart to prevent copy number changes and
chromosome fragility. Thus it is of critical importance to study restart at structure-forming
repeats as they are hotspots for mutation in the genome, and their expansion can cause
degenerative diseases such as Huntington's disease, myotonic dystrophy, and ALS. In addition,
structure-forming repeats are fragile sites that can break and provoke deletion of vital DNA
sequences during early steps of cancer initiation, which is exacerbated by replication stress
occurring in cancer cells. The outcome of this research will be a better understanding of cellular
mechanisms used to cope with replication stress, and how these mechanisms can go wrong to
cause genetic mutation. This information should provide insights into how to bolster or interfere
with these processes, to either prevent mutation or target mutated cells for elimination.

## Key facts

- **NIH application ID:** 9920163
- **Project number:** 5R01GM122880-04
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** CATHERINE H FREUDENREICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,393
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920163

## Citation

> US National Institutes of Health, RePORTER application 9920163, Fork Restart at Replication Barriers and Effects on Genome Stability (5R01GM122880-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9920163. Licensed CC0.

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