A Compendium of G-flipon Biological Functions that have Experimental Validation

As with all new fields of discovery, work on the biological role of G-quadruplexes (GQ) has produced a number of results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly because they are different from commonly held expectations. Like other classes of flipons, those that form G-quadruplexes have a repeat sequence motif that enables the fold. The canonical DNA motif (G3N1-7)3G3, where N is any nucleotide and G is guanine, a feature that is under active selection in avian and mammalian genomes. The involvement of G-flipons in genome maintenance traces back to the invertebrate C. elegans and to ancient DNA repair pathways. A role for GQ in transcription is supported by the observation that yeast Rap1 protein binds both B-DNA, in a sequence-specific manner, and GQ, in a structure-specific manner, through the same helix. Other sequence-specific transcription factors (TF) also engage both conformations. RNAs can also modulate GQ formation in a sequence-specific manner and engage the same cellular machinery as localized by TF, linking the ancient RNA world with the modern protein world. The coevolution of both sequence-specific RNA and proteins is supported by studies of early embryonic development, where the transient formation of G-quadruplexes potentially coordinates the epigenetic specification of cell fate.