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First Generation Tools for the Modeling of Capicua (CIC) - Family Fusion Oncoprotein-Driven Cancers
Cuyler Luck1,2, Kyle A Jacobs1,3, Julia Riad2,4
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
Biorxiv : the Preprint Server for Biology
|June 4, 2025
Summary
Synthetic gene fusions like CIC::NUTM1 and ATXN1::DUX4 reveal how CIC-rearrangements cause distinct cancers. These tools help study rare cancer subtypes by dissecting fusion oncoprotein activity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clinical presentation of CIC-rearrangement cancers varies, with CIC::DUX4 linked to soft tissue tumors and CIC::NUTM1 to CNS tumors.
- The molecular basis for these clinical differences is unclear due to limited research tools.
Purpose of the Study:
- To generate and validate synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 fusions.
- To investigate the structure-function relationships of novel CIC-family fusion oncoproteins.
Main Methods:
- Generation of patient-informed synthetic coding sequences for specific CIC-family gene fusions.
- Structure-function studies to validate the synthetic sequences and analyze their biological activity.
Main Results:
- CIC::NUTM1 activates a distinct transcriptional program compared to CIC::DUX4, mediated by the NUTM1 C-terminal domain.
- CIC::LEUTX exhibits weak activation of CIC target genes via LEUTX transactivation sequences.
- ATXN1::DUX4 upregulates CIC target genes through the ATXN1 AXH domain.
Conclusions:
- The binding partner in CIC fusions significantly influences the oncoprotein's activity and downstream effects.
- Developed synthetic tools offer a novel resource for studying CIC-family fusions beyond CIC::DUX4.
- These tools enable detailed dissection of rare cancer subgroups driven by CIC-family gene rearrangements.
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