How actinomycin binds to DNA and exerts its mechanism of action
In this remarkably simple and profound article — recently appearing in the March issue of the Journal of Structural and Functional Genomics — Henry M. Sobell describes his theory for the existence of “premeltons” in DNA — this providing a unifying explanation of much of DNA physical-chemistry and molecular-biology.
Key among these — is an understanding of how the anticancer agent actinomycin D binds to DNA and exerts its mechanism of action. His photo in Figure 1 — taken a number of years ago – shows Professor Sobell holding CPK space filling molecular models of actinomycin intercalating into (what he has called) the beta-DNA structural-form – this being a metastable and hyperflexible liquid-like phase that acts as a transition-state intermediate in DNA melting.
As can be seen in Figure 2, actinomycin binds to the highest-energy beta-DNA form found within the boundaries connecting double-stranded B-DNA with single-stranded DNA in the transcription complex. This immobilizes (i.e., “pins”) the complex, interfering with the elongation of growing RNA-chains. In nucleolar genes, where there be as many as 200 RNA polymerases moving down the DNA template while synthesizing growing ribosomal RNA-chains — positive and negative superhelical DNA regions between them annihilate one-another — causing adjacent transcription-complexes to bond-together to form “trains” of transcription-complexes, these now moving synchronously along DNA. If this were the case, then the binding by one actinomycin molecule is sufficient to stop the entire “transcription-train” from moving along DNA.
This insight is among many others that can be found in this fascinating article published by Professor Sobell.
Henry M. Sobell
Departments of Chemistry and Molecular Biophysics
University of Rochester
Premeltons in DNA.
J Struct Funct Genomics. 2016 Mar