title: Minor groove binder distamycin remodels chromatin but inhibits transcription.
abstract: The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as "chromatin remodeling". In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance.
authors: Biophysics Division, Saha Institute of Nuclear Physics, Kolkata, West Bengal, India.
authors: Parijat
authors: P
authors: Majumder
authors: Amrita
authors: A
authors: Banerjee
authors: Jayasha
authors: J
authors: Shandilya
authors: Parijat
authors: P
authors: Senapati
authors: Snehajyoti
authors: S
authors: Chatterjee
authors: Tapas K
authors: TK
authors: Kundu
authors: Dipak
authors: D
authors: Dasgupta
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004214:Distamycins / Q000378:metabolism / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D008297:Male; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002843:Chromatin; D004214:Distamycins; D006657:Histones; C030000:stallimycin; D000255:Adenosine Triphosphate; D004247:DNA