The basic Helix-Loop-Helix/PER-ARNT-SIM (bHLH-PAS) domain family of transcription factors
mediates cellular responses to a variety of internal and external stimuli. As functional transcription factors,
these proteins act as bHLH-PAS heterodimers and can be further sub-classified into sensory/activated
subunits and regulatory or ARNT-like proteins. This class of proteins act as master regulators of the bHLHPAS
superfamily of transcription factors that mediate circadian rhythm gene programs, innate and adaptive
immune responses, oxygen-sensing mechanisms and compensate for deleterious environmental exposures.
Some contribute to the etiology of human pathologies including cancer because of their effects on cell growth
and metabolism. We will review the canonical roles of ARNT and ARNT-like proteins with an emphasis on
coactivator selectivity and recruitment. We will also discuss recent advances in our understanding of noncanonical
DNA-binding independent or off-target roles of ARNT that are uncoupled from its classic
heterodimeric bHLH-PAS binding partners. Understanding the DNA binding-independent functions of ARNT
may identify novel therapeutic options for the treatment of a large spectrum of disease states.
Keywords: ARNT, bHLH-PAS, circadian rhythm, cross-talk, environmental sensor, oxygen sensing, transcription factor.
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