# PIWI - Transposon regulation by epithelial adherens junctions

> **NIH NIH R21** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $174,728

## Abstract

PROJECT SUMMARY
Transposon activity accounts for genomic instability in more than 50% of epithelial cancers. However, the
reasons of this activity are still unclear. The E-cadherin-based adherens junctions are essential structural
components of the epithelial cells and frequently compromised in tumors. We have found association of cadherin
junctions with PIWIL2, a key component of the piRNA-processing pathway that is responsible for silencing of
transposable elements. piRNAs comprise the largest class of small RNAs and have been extensively studied in
the germline; however, their roles in somatic tissues are unclear. Our preliminary data reveal localization of
PIWIL2 at the mature apical adherens junctions of well-differentiated breast, kidney and colon epithelial cells,
whereas this localization is lost in cancer cells. Interestingly, E-cadherin depletion results in loss of junctional
localization of PIWIL2, in upregulation of a transposable element, and increased levels of γ-H2AX, which is an
indicator of DNA damage. A hallmark of increased transposon activity is DNA double-stranded breaks. We
hypothesize that the adherens junctions recruit PIWIL2 to suppress transposon activity in differentiated epithelial
cells to maintain genomic integrity and the normal epithelial phenotype. We will test this hypothesis under the
following Aims: 1) examine whether E-cadherin suppress transposon levels and activity by enabling formation of
a PIWI-piRNA complex in well-differentiated epithelial cells; 2) investigate whether the junction-associated
PIWIL2 suppresses pro-tumorigenic transformation. This work is significant, since it will fill a gap in the
knowledge of the role of the PIWI-transposon regulation in differentiated epithelial tissues and in cancer. The
proposal is innovative, since it provides an unexpected mechanistic link between cell-cell adhesion, PIWI-
transposon biology and genomic integrity. In addition, it employs cutting-edge technologies, such as piRNA-
transposon sequencing, CRISPR/Cas9 genome editing, and super-resolution microscopy. The long-term goal of
this study is to identify a new mode of regulation of transposon silencing, coordinated by the adherens junctions,
which could be critical for suppression of transposon-driven mutagenesis and tumorigenesis. Successful
completion of the above Aims will help us gain insights into a new mechanism that tethers cell architecture to
genomic integrity and generate significant data for subsequent R01-level proposals.

## Key facts

- **NIH application ID:** 10140311
- **Project number:** 5R21CA246233-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Antonis Kourtidis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $174,728
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140311

## Citation

> US National Institutes of Health, RePORTER application 10140311, PIWI - Transposon regulation by epithelial adherens junctions (5R21CA246233-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140311. Licensed CC0.

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