Noncanonical Binding of Transcription Factors: Time To Revisit Specificity?

Authors

Md Abul Hassan Samee

Publication Date

8-1-2023

Journal

Molecular Biology of the Cell

DOI

10.1091/mbc.E22-08-0325

PMID

37486893

PMCID

PMC10398899

PubMedCentral® Posted Date

8-1-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

no

Keywords

Humans, Transcription Factors, DNA-Binding Proteins, Binding Sites

Abstract

Transcription factors (TFs) are one of the most studied classes of DNA-binding proteins that have a direct functional impact on gene transcription and thus, on human physiology and disease. The mechanisms that TFs use for recognizing target DNA binding sites have been studied for nearly five decades, yet they remain poorly understood. It is classically assumed that a TF recognizes a specific sequence pattern, or motif, as its binding sites. However, recent studies are consistently finding examples of noncanonical binding, that is, TFs binding at sites that do not resemble their sequence motifs. Here we review the current literature on four major types of noncanonical TF binding, namely binding based on DNA shape readout, at Guanine-quadruplex structures, at repeat sequences, and bispecific binding. These examples point to a critical need for studies to unify our current observations, many of which are at odds with the "one TF, one motif" view, into a more comprehensive definition of the DNA-binding specificity of TFs.