Association of the anticancer antibiotic chromomycin A(3)
with the nucleosome: role of core histone tail domains in the binding process.
Mir MA, Dasgupta D.
Biophysics Division, Saha Institute of Nuclear Physics, 37 Belgachhia Road,
Kolkata-700 037, India.
The anticancer antibiotic chromomycin A(3) is a transcription inhibitor which
forms two types of complexes with Mg(2+): complex I (1:1 in terms of chromomycin
A(3)-Mg(2+)) and complex II (2:1 in terms of chromomycin A(3)-Mg(2+)). These
complexes are the DNA-binding ligands. With the broad objective of elucidation
of the mechanism for action of this group of transcription inhibitors in
eukaryotic systems, we have studied the interaction of the antibiotic with
nucleosome core particles under different conditions. We have demonstrated and
characterized the role of core histone proteins, particularly the N-terminal
tail domains, in the association of nucleosome with both complexes of
chromomycin. From a scrutiny of the spectroscopic features of the two bound
complexes and comparison of the binding and associated thermodynamic parameters,
we have shown the following. Core histone(s) stand(s) in the way of access of
the ligand(s) to nucleosomal DNA. N-Terminal intact and chopped core particles
interact differentially with the same complex. The modes of interaction of the
two complexes, I and II, with the same system are different. Tryptic removal of
N-terminal tail domains of core histones enhances the binding potential and
access of both complexes of chromomycin to the nucleosomal DNA. Agarose gel
electrophoresis of an equilibrium mixture containing either complex I or complex
II and a saturating concentration of the core particle has demonstrated that
both complexes have a tendency to disrupt the nucleosome structure, leading to a
release of nucleosomal DNA. Compared to the N-terminal intact nucleosome, the
N-terminal chopped nucleosome is more susceptible to disruption. Therefore, we
suggest from the above results that the N-terminal tail domains, which have an
important role in eukaryotic gene expression, stand in the way of a free access
of external agents such as anticancer drugs to the eukaryotic genome. The
significance of the results to understand the molecular basis of the
transcription inhibitory capacity of chromomycin is discussed.