SUNY at Albany
June 19-23, 2001
How the Formation of DNA Tetraplexes Turns Oncogenes On and Off
One of the first steps in the activation process of a gene is the rearrangement or disruption of the chromatin structure, which otherwise might prevent binding of the transcription machinery to the promoter. It is well established that chromatin unfolding in the promoter regions of genes is preceded by the appearance of nuclease hypersensitive elements (NHEs), whose existence are a prerequisite for gene expression as opposed to a mere reflection thereof. They are believed to represent regions devoid of canonical nucleosomes in which the DNA is exposed and more sensitive to nucleases, but mechanisms that govern their formation remain elusive. Here I present a molecular mechanism in which NHE formation and gene activation might be regarded as intimately coupled events: A major control element upstream of the human c-myc proto-oncogene is hypersensitive to nucleases and highly asymmetric, one strand is very rich in guanines and the other in cytosines. In vitro and in vivo data demonstrate how both strands form intrastrand fold-back tetraplexes, the former with a core of stacked G-quartets and the latter with intercalating hemiprotonated cytosine+-cytosine base-pairs. Together the two strands constitute an NHE that is recognized by tetraplex binding transcription factors that promote the assembly of the RNA polymerase II transcription machinery. Collectively this amounts to a mechanism, which not only explains how c-myc transcription is initiated at the molecular level, but also explains how oligonucleotide based gene therapy blocks c-myc expression. Notably the characterized motif is not unique to the c-myc promoter, but recurs as NHEs in the control regions of many proto-oncogenes.
Medical Research Council
Laboratory of Molecular Biology