The impact of chromatin in human cancer: linking DNA methylation to gene silencing

Abstract

For decades, chromatin was considered to be an inert structure whose only role was the compacting and confining of DNA inside the eukaryotic nucleus. However, tremendous progress in this field over the last 10 years has dramatically elevated chromatin to a key position in the control of gene activity. Its role in mediating the transformation of a normal cell into a malignant state is particularly interesting. On one side of this story there is the discovery that aberrant methylation patterns in an increasing number of tumour suppressor and DNA repair genes determine carcinogenetic transformation; while on the other side, there is the existence of a series of methyl-DNA binding activities that recruit co-repressor complexes and modify the structure of the chromatin to produce a transcriptionally silenced state. Although this field has seen rapid progress in recent years, detailed mechanisms by which this machinery modifies chromatin structure to its appropriate state and the specific targeting of repressor complexes have yet to be resolved. In this review we present the models of how repressor complexes may modify chromatin structure and mediate silencing of tumour suppressor and DNA repair genes.