Control of Gene Expression by Proteins That Bind Many Alternative Nucleic Acid Structures Through the Same Domain

Area of Science:

• Molecular Biology
• Genomics
• Structural Biology

Background:

• Alternative nucleic acid structures (ANS), including Z-DNA, triplexes, G-quadruplexes, and i-motifs, were historically dismissed due to lack of evidence for biological relevance.
• Transcription factors (TFs) were known to bind canonical B-DNA, with limited understanding of their interaction with ANS.
• ANS are dynamically formed by specific repeat sequences called flipons, particularly enriched in promoter regions.

Purpose of the Study:

• To investigate the potential binding of known B-DNA-binding TFs to alternative nucleic acid structures (ANS) using advanced computational modeling.
• To explore the role of ANS in gene transcription regulation and TF interactions.
• To elucidate the mechanisms by which TFs interact with ANS and how this influences genome scanning and promoter regulation.

Main Methods:

• Computational modeling utilizing AlphaFold V3 (AF3) under optimized conditions.
• Analysis of TF docking interactions with various ANS, including Z-DNA and G-quadruplexes.
• Investigation of the effect of methylarginine modifications on TF binding to Z-DNA.

Main Results:

• Known B-DNA-binding TFs, including HLH and bZIP homodimers, were shown to dock to ANS like ZNA and GQ.
• Methylarginine modifications promote the binding of HLH and bZIP homodimers to Z-DNA.
• Heterodimers were observed to bind only to preformed Z-DNA, suggesting a role in TF complex assembly.

Conclusions:

• TF interactions with ANS likely enhance genome scanning for cognate B-DNA sites in active genes.
• Docking to Z-DNA may facilitate the assembly and stabilization of TF heterodimers, enabling rapid discovery of optimal combinations for promoter regulation.
• This study highlights a novel mechanism for gene regulation involving dynamic ANS and their interactions with transcription factors.