DNA Structural Topology as a Mechanical Control Channel for Processive Enzymes: A Hypothesis for Shape-Dependent Traversal Signaling

This paper proposes that sequence-dependent variation in DNA helical geometry—including minor groove width, propeller twist, roll, tilt, and local rigidity—constitutes a discrete mechanical signaling channel read by processive enzymes during translocation along the double helix. This channel operates alongside and distinct from both base-sequence readout and epigenetic mark readout. Existing research has characterized DNA shape readout primarily in the context of transcription factor binding-site selection, asking why a protein binds at one location rather than another. The present hypothesis reframes DNA shape as a continuous control signal encountered during enzymatic traversal, proposing that structural features function as mechanical gates that activate, deactivate, or modulate enzymatic behavior at specific positions along the strand. The hypothesis generates a concrete, falsifiable prediction: that germline reprogramming enzymes (DNMT3A, TET1/2/3) will exhibit measurable processivity variation and pause signatures that correlate with computed DNA shape parameters at reprogrammed loci, detectable by single-molecule translocation assays benchmarked against shape prediction algorithms such as Deep DNAshape. If confirmed, this would establish DNA structural topology as a third information layer—alongside nucleotide sequence and epigenetic modification—encoding positional control instructions for the molecular machinery that maintains, remodels, and interprets the genome.