Unstructured but critical: The role of YY1 and YY2 disorder in promoter recognition networks, transcriptional control, and oncogenesis

Abstract

The transcription factors Yin Yang 1 and Yin Yang 2 are key regulators of gene expression and play complex roles in cancer development. Although closely related in sequence and structure, YY1 and YY2 differ in their degree of intrinsic disorder, interaction profiles, and regulatory potential. Both proteins are subject to cancer-associated alterations, including changes in expression levels and somatic mutations, many of which correlate with clinical outcomes.

This review synthesizes a comparative analysis of YY1 and YY2, with a focus on their disordered regions, interaction networks, and promoter targeting mechanisms. YY1 exhibits a higher degree of intrinsic disorder and a greater number of predicted Molecular Recognition Features (MoRFs), enabling a broader and more competitive range of interactions. YY2, in contrast, is more structurally ordered and engages a more limited set of partners. While both proteins recognize specific and highly similar DNA motifs, their binding is relatively weak, and functional specificity is conferred primarily through distinct protein–protein interactions and regulatory complex assembly.

We integrate these findings within the framework of Brodsky's model of promoter recognition, which emphasizes the role of dynamic, cooperative interactions in guiding transcription factor specificity. By mapping cancer-associated mutations and post-translational modifications onto functional regions, we highlight how such alterations may disrupt interaction networks and promoter selection. Finally, we explore the therapeutic potential of selectively targeting YY1/YY2 interactions, despite the challenges posed by their intrinsically disordered domains.