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

Sep 21, 2026

Uploaded by Maeve

Cancer initiation and progression often involve driver mutations and genomic instability, but some cancers arise from epigenetic alterations alone. This study addresses whether prolonged loss of PRC1 after a transient downregulation event leads to eventual instability. Prolonged depletion of PH, modeling cancer-initiating conditions, causes broad dysregulation of DNA replication and repair genes, DNA break accumulation, defective repair, and widespread genomic instability. It also disrupts H2AK118 ubiquitylation and, to a lesser extent, H3K27 trimethylation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

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Abstract

Keywords

Introduction

Polycomb complexes and cancer relevance

PRC1 in DNA double-strand break repair

Histochemistry and Cell Biology (2024) 162:133–147 [https://doi.org/10.1007/s00418-024-02302-z](https://doi.org/10.1007/s00418-024-02302-z) Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors Chetan C. Rawal1 · Vincent Loubiere2,3 · Nadejda L. Butova1 · Juliette Gracia2 · Victoria Parreno2 · Chiara Merigliano1 · Anne‑Marie Martinez2 · Giacomo Cavalli2 · Irene Chiolo1 Accepted: 27 May 2024 / Published online: 18 June 2024 © The Author(s) 2024 Abstract Cancer initiation and progression are typically associated with the accumulation of driver mutations and genomic instability. However, recent studies demonstrated that cancer can also be driven purely by epigenetic alterations, without driver mutations. Specifically, a 24-h transient downregulation of polyhomeotic (ph-KD), a core component of the Polycomb complex PRC1, is sufficient to induce epigenetically initiated cancers (EICs) in Drosophila, which are proficient in DNA repair and characterized by a stable genome. Whether genomic instability eventually occurs when PRC1 downregulation is performed for extended periods of time remains unclear. Here, we show that prolonged depletion of PH, 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 misregulation 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 accumulate during the tumorigenic transformation epigenetically induced by PRC1 loss, resulting in genomic instability and cancer progression. Keywords Epigenetically initiated cancers · Polycomb complex · Double-strand break repair · Genomic instability Introduction The tumorigenic process is typically associated with DNA damage defects and genomic instability (Hopkins et al. 2022) . However, recent studies established that cancer can Chetan C. Rawal and Vincent Loubiere have contributed equally to this work. * Anne-Marie Martinez [anne-marie.martinez@igh.cnrs.fr](anne-marie.martinez@igh.cnrs.fr) * Giacomo Cavalli [giacomo.cavalli@igh.cnrs.fr](giacomo.cavalli@igh.cnrs.fr) * Irene Chiolo[chiolo@usc.edu](chiolo@usc.edu) 1 Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089, USA 2 Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France 3 Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria also be induced purely by epigenetic changes initiated by the transient loss of the transcriptionally repressive Polycomb PRC1 complex (Parreno et al. 2024) . Polycomb Group (PcG) proteins are grouped in two main classes of complexes called Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2) (Levine et al. 2002 ; Kassis et al. 2017 ; Schuettengruber et al. 2017) . Drosophila PRC1, which is composed of PH, PC, PSC, and SCE subunits, is primarily responsible for H2AK118 ubiquitylation (H2AK118ub, corresponding to H2AK119ub in mammals) (Barbour et al. 2020 ; Parreno et al. 2022), whereas PRC2 mediates H3K27 trimethylation (H3K27me3) (Holoch and Margueron 2017) . PRC1 and PRC2 are also highly interdependent, given that PRC1 binds to H3K27me3 while PRC2 associates with H2AK118ub (Blackledge et al. 2014 ; Cooper et al. 2016, Kasinath et al. 2021) . This enables cooperative binding of the two complexes to the same sites and codependency in the establishment of the respective marks on chromatin (Cooper et al. 2016; Barbour et al. 2020, Tamburri et al. 2020) . While PRC1 and PRC2 form several redundant subcomplexes in mammalian cells (Parreno et al. 2022, Potter et al. 2023), Drosophila Polycomb complexes comprise a reduced number of paralogous and ac

FAQs

What question does the study investigate about PRC1 downregulation?

It examines whether genomic instability occurs when PRC1 downregulation is maintained for extended periods, beyond an initially transient event.

What happens after prolonged depletion of PH in the cancer tissue?

PH depletion leads to dysregulation of DNA replication and repair genes, accumulation of DNA breaks, defective repair, and widespread genomic instability.

Which histone marks are affected by PRC1 loss and may contribute to the observed phenotypes?

The study reports broad misregulation of H2AK118 ubiquitylation and, to a lesser extent, H3K27 trimethylation.

Sep 21, 2026

Uploaded by Maeve