John H. Frenster
Laboratory of Cell Biology
Rockefeller Institute
New York, NY 

These strong correlations suggest that such ligands may exert their characteristic effects on RNA synthesis by preferentially stabilizing either the inactive helical form or the active loop form of DNA (2, 10) in the equilibrium:

The mechanisms of such preferential binding to either double-stranded helical DNA or to single-stranded loop DNA are little understood. Preliminary thermodynamic analyses have revealed that the equilibrium between the helical and the loop forms of DNA can be shifted during binding by an effect of the ligand on one or more of the physical forces existing within the DNA-solvent system. These forces include:

(a). The hydrophobic solute-solvent interactions between DNA and water (19);

(b). The hydrogen bond interactions between the complementary bases of the opposing DNA strands (20);

(c). The electrostatic charge interactions between the phosphate groups of the same or opposing DNA strands (21);

(d). The stacking (van der Waal's) interactions between the successive bases of the same or opposing DNA strand (22).

In addition, the ability of particular ligands to:

(e). Cross-link opposing DNA strands (23), or to:

(f). Fit sterically into certain regions of the DNA molecule (23)

is of importance in the inhibition or stimulation of RNA synthesis. Thus, both histone-type inhibitors and actinomycins bind preferentially to double-stranded helical DNA by utilizing properties (e) and (f) (23). In addition, histones alter physical force (c) (3), while actinomycins may alter forces (a), (c) and (d) (6). By contrast, both testosterone-type stimulators and oestradiol-type stimulators bind preferentially to single-stranded loop DNA by utilizing property (f) (24), and by altering physical forces (a) and (d) (24). Before such inhibitors or stimulators can bind to DNA and alter the rates of RNA synthesis they must often be first concentrated within the particular sensitive tissue by specific, non-DNA binding agents (12, 25).

All the foregoing inhibitory or stimulatory ligands (Table 1) except complementary RNA are molecules which are capable of reacting with all portions of the DNA genome non-selectively. RNA by contrast is capable of a selective interaction with specific portions of the DNA genome (17). It is this selective ability which appears to be the basis for its role as the agent of specific de-repression of RNA synthesis during selective transcription of the genome (1, 2, 18). In a similar fashion, polyoma viral DNA binds preferentially to single-stranded host DNA (26). The result of such oncogenic viral DNA interaction with the host DNA genome is a de-repression of host DNA synthesis and of host enzyme synthesis (27, 28). A concurrent selective de-repression of host RNA synthesis is also likely (27).

This work was carried out during the tenure of a research career development award (CA 17857) from the U.S. Public Health Service.

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28. Kit S, Dubbs DR, Anken M, and Melnick JL, J. Cell Biol. 27: 52A (1965). 

Additional References:

1. Frenster JH, Nature 205: 1341 (1965).