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The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

ABSTRACT: The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

PROVIDER: PRJNA1172903 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30992942_1.fastq.gz	Fastqsanger.gz
	SRR30992942_2.fastq.gz	Fastqsanger.gz
	SRR30992943_1.fastq.gz	Fastqsanger.gz
	SRR30992943_2.fastq.gz	Fastqsanger.gz
	SRR30992944_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

Project description:Transcription factor (TF) fusion oncoproteins represent cancer specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. Thus, WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC:DUX4 mediated tumor growth in vitro and tumor formation in vivo. Altogether, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.

2024-10-16 | GSE279467 | GEO

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.

Project description:Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

2024-10-16 | GSE279546 | GEO

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

2024-06-06 | GSE269295 | GEO

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model

Project description:Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model

| PRJNA1007765 | ENA

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (RNA-Seq)

Project description:CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies is limited by the scarcity of tissues and patients. To minimize, we made three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease authenticating them as CDS. Lastly, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator and point to ETS family transcription factors as cooperative and redundant drivers of the core regulatory circuitry.

2023-10-19 | GSE241369 | GEO

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (ChIP-Seq)

2023-10-19 | GSE241370 | GEO

Modeling cancer-associated mutations reveals an integrated role for the Pol epsilon catalytic core in replisome assembly and DNA synthesis

Project description:DNA polymerase epsilon (Pol epsilon) plays multiple roles in genome duplication and its catalytic subunit POLE suppresses tumorigenesis in humans. Despite its importance, we have limited understanding of Pol epsilon functional mechanisms and how its loss-of-function affects the evolution of cancer genomes. To address this issue, we used the budding yeast ortholog Pol2 to model cancer-associated POLE mutations that affect an uncharacterized yet highly conserved Pol2/POLE family-specific region. Analysis of pol2 mutants revealed an unexpected role for this region in the incorporation of Pol epsilon into the pre-loading complex during replisome assembly. Cellular and reconstitution experiments further identified a separate role for this region in promoting Pol epsilon polymerase activity. Unlike previously reported POLE mutations leading to hypermutation in cancer cells, the examined pol2 variants increase gross chromosomal rearrangements but not mutation rates. Our findings thus suggest that the Pol epsilon catalytic core integrates replisome assembly and DNA polymerization functions and that POLE tumor suppressive roles likely extend beyond limiting replication errors.

2020-03-29 | GSE132450 | GEO

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (RNA-Seq)

Project description:Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (RNA-Seq)

| PRJNA1007764 | ENA

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (ChIP-Seq)

Project description:Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (ChIP-Seq)

| PRJNA1007767 | ENA

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

Project description:The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

| PRJNA1120911 | ENA