BCOR-Rearranged Sarcomas : In Silico Insights into Altered Domains and Reduced RAWUL-PUFD Binding

Madarász, Kristóf and Mótyán, János András and Chien, Yi-Che Chang and Bedekovics, Judit and Csoma, Szilvia Lilla and Méhes, Gábor and Mokánszki, Attila (2024) BCOR-Rearranged Sarcomas : In Silico Insights into Altered Domains and Reduced RAWUL-PUFD Binding. BIORXIV. ISSN 2692-8205 (In Press)

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Abstract

BCOR (BCL-6 corepressor)-rearranged small round cell sarcoma (BRS) is a rare soft tissue tumor, mostly featuring the BCOR::CCNB3 fusion, with other fusions like BCOR::MAML3, BCOR::CLGN, ZC3H7B::BCOR, KMT2D::BCOR, CIITA::BCOR, and RTL9-BCOR also reported. BCOR, a Polycomb Repressive Complex 1 (PRC1) component, influences histone modifications. It dimerizes with Polycomb group RING finger homolog (PCGF1) via its PCGF ubiquitin-like fold discriminator (PUFD) domain interacting with PCGF1’s RING finger and WD40-associated ubiquitin-like (RAWUL) domain. We used various in silico tools to explore the impact of fusion events on BCOR’s functionality and RAWUL-PUFD dimer binding affinity. Changes were found in the domain landscapes, physicochemical properties, GO terms and significant increases in the disordered regions within the PUFD domain of the fusion proteins. Structural predictions indicated modified intermolecular contacts (ICs) and a significant reduction in binding affinity in fusion protein RAWUL-PUFD dimers. These findings align with expression data showing PRC1-regulated gene upregulation in BRS, likely due to reduced RAWUL-PUFD binding affinity, impacting dimer formation and PRC1 assembly. Our findings enhance the understanding of BRS oncogenesis and identify potential therapeutic targets.

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