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Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic
Chetan C Rawal1, Vincent Loubiere2,3, Nadejda L Butova1
1Department of Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089, USA.
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.
Insights
Prolonged polyhomeotic depletion in Drosophila epigenetically initiates cancer. This leads to DNA repair defects and genomic instability, driving cancer progression without initial mutations.
Area of Science:
- Epigenetics and Cancer Biology
- Genomics and DNA Repair Mechanisms
- Developmental Biology (Drosophila Model)
Background:
- Cancer is often linked to genetic mutations and instability.
- Epigenetic alterations alone can initiate cancer, independent of mutations.
- Polycomb Repressive Complex 1 (PRC1) and polyhomeotic (PH) play crucial roles in epigenetic regulation.
Purpose of the Study:
- To investigate the long-term consequences of PRC1 downregulation on genome stability.
- To determine if prolonged epigenetic alterations lead to genomic instability in epigenetically initiated cancers (EICs).
- To elucidate the molecular mechanisms linking PH loss to cancer progression.
Main Methods:
- Utilizing Drosophila melanogaster as a model organism.
- Implementing prolonged depletion of polyhomeotic (PH) to mimic cancer initiation.
- Analyzing DNA replication and repair gene expression.
- Assessing DNA breaks and repair efficiency.
- Evaluating epigenetic marks like H2AK118 ubiquitylation and H3K27 trimethylation.
Main Results:
- Prolonged PH depletion caused broad dysregulation of DNA replication and repair genes.
- Accumulation of DNA breaks and defective DNA repair were observed in cancer tissues.
- Widespread genomic instability was a hallmark of prolonged PH depletion.
- Misregulation of H2AK118 ubiquitylation and H3K27 trimethylation correlated with observed phenotypes.
Conclusions:
- Epigenetic silencing of PRC1, when prolonged, induces DNA repair and replication defects.
- These defects contribute to genomic instability and cancer progression.
- This study supports a model where epigenetic changes drive cancer through accumulating DNA damage and instability.
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