# The cross-regulation of host DNA replication and LTR Retrotransposons

> **NIH NIH R35** · RUTGERS, THE STATE UNIV OF N.J. · 2022 · $388,533

## Abstract

Project summary
 The proposed work is part of our long-term goal to understand host-transposon interactions
that influence eukaryotic genome function and evolution.
 Retrotransposons are a class of transposable element capable of amplifying their copy number
via reverse-transcription of RNA intermediates and insertion in a new locus. Through this
transposition activity, they can multiply to the point of making up the majority of genetic material in
some genomes, exerting a broad influence in genome structure and regulation. The repetitive nature
of TE can also affect genome integrity through homologous recombination between their dispersed
copies that can cause chromosomal rearrangements. To counteract their deleterious effects,
eukaryotes have evolved multiple genome defense mechanisms that suppress Retrotransposon
activity. The most important are RNA interference (RNAi) pathways that are often specifically active
in the germline, protecting the genetic material that will make up the next generation.
 We are investigating these host-Retrotransposon interactions using the LTR Retrotransposons
Tf1 and Tf2, endemic to fission yeast. In previous work, we have revealed an intense cross-regulation
between the Retrotransposon and the process of host DNA replication, discovering how
Retrotransposons select new insertion sites, regulate chromatin silencing, and control homologous
recombination. Several aspects of these phenomena are conserved in LTR retrotransposons present in
the genomes of other organisms, even while the specific factors involved are not. This suggests that
common evolutionary pressures lead to convergent evolution of host-Retrotransposon interactions.
As a consequence, these conserved mechanisms may be important for metazoan germline stability.
 In the present application, we propose a comprehensive line of research combining genetics,
biochemistry, and high throughput sequence-based genomics methods to (1) ascertain universal
Retrotransposon insertion site selection mechanisms, (2) resolve the determinants of LTR
Retrotransposon detection by RNAi, (3) determine the mechanism by which Retrotransposons guide
their own homologous recombination, and (4) investigate the effect of Retrotransposon activity in
meiosis progression. In pursuit of these goals, we will make use of novel fission yeast strains in which
all Retrotransposon copies have been deleted through an innovative CRISPR mutagenesis method.
This advance enables us to carry out previously unfeasible genetic analyses of these highly repetitive
elements. The proposed studies will provide a novel and comprehensive understanding of host-
Retrotransposon interactions, and their consequences on genome regulation and stability.

## Key facts

- **NIH application ID:** 10406993
- **Project number:** 5R35GM131763-04
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** MIGUEL ANGEL ZARATIEGUI BIURRUN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,533
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406993

## Citation

> US National Institutes of Health, RePORTER application 10406993, The cross-regulation of host DNA replication and LTR Retrotransposons (5R35GM131763-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406993. Licensed CC0.

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