# Mechanisms of Genome Instability Mediated by Simple DNA Repeats

> **NIH NIH R35** · TUFTS UNIVERSITY MEDFORD · 2020 · $78,592

## Abstract

Abstract of the Parent Funded Award
Expansions of simple DNA repeats are implicated in more than thirty hereditary neurological
and neurodegenerative disorders in humans. Hundreds of copies of the causative repeat can be
added in just a few intergenerational transmissions. Thus, understanding the mechanisms
responsible for large-scale repeat expansions is extremely important and has broad biomedical
implications. My lab was the first to show that expandable DNA repeats stall replication fork
progression in every experimental system studied, including bacteria, yeast and mammalian
cells. This led us to propose that repeats can be added while the replication fork escapes from a
“repetitive trap”. Early models of repeat expansion involved slippage of repetitive DNA strands,
which is normally small-scale, during DNA replication. Based on the size of expansions
observed in humans, we believe that a distinct mechanism could cause large jumps in the
repeat’s size. To substantiate this idea, we developed an experimental system for large-scale
repeat expansions in a model organism, S. cerevisiae. This system uncovered features of
repeat expansions similar to that observed in human pedigrees. The rate of expansions
increased exponentially with their lengths. Repeat expansions become evident, when the length
of a repeat exceeds the Okazaki fragment size, which is close to the repeat expansion threshold
in humans. The majority of genes involved in repeat expansions appear to encode proteins of
the replication or post- replication repair machineries. These observations led us to outline two
pathways for large-scale repeat expansions based on either template-switching during DNA
replication, or break-induced replication. Capitalizing on these achievements, we plan to move
our research in three new directions. First, we are developing a novel experimental strategy to
analyze repeat instability in non-dividing, chronologically aging yeast cells. Repeat expansions
are known to occur in post-mitotic tissues, such as the brain, and they are believed to contribute
to disease pathogenesis. Thus, understanding the genetic controls and mechanisms of repeat
expansions in non-dividing cells is invaluable for understanding the pathobiology of these
diseases. Second, we are working on establishing a genetically tractable system to analyze the
mechanisms of large-scale repeat expansions in cultured mammalian cells. We will then look at
the effect of candidate genes, which were identified in our yeast screens, on repeat expansions
in mammalian cells using siRNA gene knockdown. Finally, while the length of an expandable
repeat is the key factor determining disease inheritance, recent clinical genetics data point to
the existence of trans-modifiers that can affect the likelihood of repeat expansions and disease
progression. We will, therefore, identify trans-modifiers of repeat expansion at the genome-wide
level in our yeast experimental system. Identification of such trans-mo...

## Key facts

- **NIH application ID:** 10116680
- **Project number:** 3R35GM130322-02S1
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** SERGEI MIRKIN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,592
- **Award type:** 3
- **Project period:** 2019-03-14 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116680

## Citation

> US National Institutes of Health, RePORTER application 10116680, Mechanisms of Genome Instability Mediated by Simple DNA Repeats (3R35GM130322-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116680. Licensed CC0.

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