# Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors

## TL;DR

This study shows that long-term inactivation of the PRC1 complex leads to DNA repair issues and genomic instability in epigenetically driven cancers.

## Contribution

The novel finding is that sustained PRC1 down-regulation, unlike transient depletion, causes DNA repair defects and genomic instability.

## Key findings

- Prolonged PRC1 depletion causes dysregulation of DNA replication and repair genes.
- Extended PRC1 loss leads to DNA breaks and widespread genomic instability.
- Mis-regulation of H2AK118 ubiquitylation and H3K27 trimethylation may contribute to these defects.

## Abstract

Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancers can also be purely initiated by epigenetic alterations, without driver mutations. Specifically, a 24-hours transient down-regulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to drive epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and are characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 down-regulation is performed for extended periods of time remains unclear. Here we show that prolonged depletion of a PRC1 component, which mimics cancer initiating events, results in broad dysregulation of DNA replication and repair genes, along with the accumulation of DNA breaks, defective repair, and widespread genomic instability in the cancer tissue. A broad mis-regulation of H2AK118 ubiquitylation and to a lesser extent of H3K27 trimethylation also occurs, and might contribute to these phenotypes. Together, this study supports a model where DNA repair and replication defects amplify the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression.