The role of nuclear organization in cancer

Abstract

The functional significance of changes in nuclear structure and organization in transformed cells remains one of the most enigmatic questions in cancer biology. In this review, we discuss relationships between nuclear organization and transcription in terms of the threedimensional arrangement of genes in the interphase cancer nucleus and the regulatory functions of nuclear matrix proteins. We also analyse the role of nuclear topology in the generation of gene fusions. We speculate that this type of multi-layered analysis will one day provide a framework for a more comprehensive understanding of the genetic origins of cancer and the identification of new therapeutic targets.

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

“…More probably, specific interphase chromosome organization is rather an element of a pathogenetic pathway rather than a unique underlying disease cause. This idea is further supported by observations on diseases caused by mutations in genes encoding chromatin architecting and remodeling proteins [17] and generation of cancer-causing chromosomal rearrangements [18].…”

“…Therefore, it is not surprising that a number of diseases associated with genetic defects in genes encoding chromatin architecting and remodeling proteins [17] as well as diseases characterized by genome and/or chromosome instability (i.e. cancers) are hallmarked by alterations to spatial genome organization in interphase nuclei [18]. These are suggested to result from failure of genome maintenance and DNA repair machineries, which also depend on interphase chromosome architecture [19].…”

“…These are suggested to result from failure of genome maintenance and DNA repair machineries, which also depend on interphase chromosome architecture [19]. On the other hand, specific chromosome positioning (intermingling Visualization of interphase chromosomes of chromosome territories) is considered as a mechanism of promoting cancer-causing interchromosomal translocations [8,10,11,18]. Furthermore, interphase chromosome associations (somatic pairing) seem to be involved in regulation of transcriptional activity within specific chromosomal regions including imprinted genomic loci, known to be linked to hereditary diseases and cancer [20].…”

An introduction to genes, genomes and disease

“…The simple concept that the nucleus is merely a haphazard arrangement of DNA and histones was long ago dispelled and we now recognize that there is a well-defined architecture and structure to this organelle. Lever and Sheer [9] overview this topic and provide a clear review of the essential anatomy of the nucleus and how this modulates its physiology and pathophysiology. The unravelling of these largescale factors is but one part of our new genetic insight into cellular physiology.…”

“…The organization of the nucleus with the definition of chromosome territories and domains is increasingly recognized, and perturbation of this is increasingly seen as important in cancer biology [9]. Furthermore, in the last few years our understanding of somatic gene rearrangements as pathogenetic factors in cancer has grown beyond the examples seen in leukaemia and lymphoma, and Edwards reviews this area for us [40], highlighting the developing concept that such rearrangements may be much more prevalent in epithelial malignancies than we had hitherto suspected.…”