# Mechanisms of Genome Instability Mediated by Simple DNA Repeats

> **NIH NIH R35** · TUFTS UNIVERSITY MEDFORD · 2020 · $548,282

## Abstract

Project Summary
 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-modifiers is poten...

## Key facts

- **NIH application ID:** 9893926
- **Project number:** 5R35GM130322-02
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** SERGEI MIRKIN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $548,282
- **Award type:** 5
- **Project period:** 2019-03-14 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893926

## Citation

> US National Institutes of Health, RePORTER application 9893926, Mechanisms of Genome Instability Mediated by Simple DNA Repeats (5R35GM130322-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893926. Licensed CC0.

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