The structural, functional, and regulatory insight of deubiquitinating enzyme - USP22.

Ubiquitination is essential for the regulation of numerous cellular functions, including transcriptional regulation, progression of the cell cycle, and immunity. This intricate process is meticulously governed by ubiquitin-conjugating enzymes (UBCs) and deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 22 (USP22), a vital member of the Ubiquitin protease system (UPS) family, effectively regulates diverse cellular processes through its deubiquitinase activity. It also contributes significantly to the regulation of transcription by histone modification. USP22 serves as a catalytic component of the human Spt-Ada-Gcn5 Acetyltransferase (hSAGA) complex, playing a vital role in transcriptional regulation by affecting the ubiquitination and methylation of histones, thereby regulating gene expression. This review focused on the structural information of the SAGA complex and its involvement in transcription, cell cycle progression, and cancer. It delves into the structural integration of their regulatory motifs, ubiquitin-binding domains, and zinc finger motifs, and it also facilitates substrate recognition and catalysis. We highlighted the detailed oncogenic role of USP22 in various cancers and its impact on various key signaling pathways, including c-Myc. By integrating structural and functional insights, this review aims to advance the understanding of USP22 structural makeup and its role in various cancers, which stabilizes as a potential drug target, providing the foundation for future research and drug development.