Nucleolar organization, growth control and cancer

Abstract

The nucleolus is a dynamic region of the nucleus that is disassembled and reformed each cell cycle and whose size is correlated with cell growth rate. Nucleolar size is a prognostic measure of cancer disease severity and increasing evidence suggests a causative role of nucleolar lesions in many cancers. In recent work (Shiue et al. Oncogene 28, 1833-42, 2009) we showed that the c-Myc oncoprotein induces changes in the higher order structure of rDNA chromatin in the nucleolus of growth stimulated quiescent rat cells. Here we show that c-Myc induces similar changes in human cells, that c-Myc plays a role in the overall structural integrity of the nucleolus and that c-Myc and its antagonistic partner Mad1 interact to program the epigenetic status of rDNA chromatin. These changes are discussed in relation to current knowledge about nucleolar structure as well as the organization of chromosomes and transcription factories in nuclear regions outside the nucleolus.

Myc-induced anchorage of the rDNA IGS region to nucleolar matrix modulates growth-stimulated changes in higher-order rDNA architecture

“…We wondered whether the nuclear matrix might be involved in the growth-regulated higher-order chromatin structure of the rDNA (8,9,26). The MAR-Wiz algorithm (27,28,29) predicts that the main potential for matrix attachment within the rDNA is restricted to the non-transcribed IGS in human (Figure 1A) and mouse rDNA (Supplementary Figure S1).…”

Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer

“…An increase in size and number of nucleoli was one of the earliest hallmarks of cancer identified and is still a useful prognostic indicator today 6 . The nucleolus is the primary site of ribosomal biogenesis and enlarged nucleoli correlate with accelerated ribosomal RNA (rRNA) synthesis by RNA polymerases 6,7 .…”

“…The nucleolus is the primary site of ribosomal biogenesis and enlarged nucleoli correlate with accelerated ribosomal RNA (rRNA) synthesis by RNA polymerases 6,7 . Synthesis of ribosomes is one of the most complex and energy demanding processes in cells.…”

847 Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation

“…Whether other molecular alterations that affect the epigenetic state of the rDNA loci also affect nucleolar dynamics in prostate cancer, and precisely how MYC can regulate nucleolar size, number and function awaits additional studies. Interestingly, recent findings are beginning to elucidate how MYC affects rRNA transcription by both inducing gene loop structures in rDNA chromatin that juxtaposes upstream and downstream rDNA sequences, as well as, by inducing other changes in chromatin structure including histone modifications (Shiue et al, 2009(Shiue et al, , 2010. By contrast to this short-term regulation, in some cases long-term regulation during development and differentiation is mediated by epigenetic mechanisms that consist of recruitment of previously inactive heterochromatic repeats to become active repeats (McStay and Grummt, 2008).…”