ABSTRACT
Ribosome biogenesis centres both physically and functionally on the activity of the ribosomal RNA (rRNA) genes. Ribosome assembly occurs co-transcriptionally on these genes, requires the coordinated expression and assembly of many hundreds of proteins and is finely tuned to cell and organism growth. This review presents contemporary understanding of the mode and the means of rRNA gene transcription and how growth factors, oncogenes and tumour suppressors regulate this transcription. It is argued that transcription elongation is a key mechanism regulating rRNA gene transcription. This unorthodox view provides a logical framework to explain the co-transcriptional phase of ribosome biogenesis.
Subject(s)
Gene Expression Regulation , Genes, rRNA , RNA, Ribosomal/biosynthesis , Ribosomes/metabolism , Animals , Base Sequence , Humans , Molecular Sequence Data , Protein Biosynthesis , RNA Polymerase I/metabolism , RNA, Ribosomal/chemistry , Ribosomes/genetics , Transcription, GeneticABSTRACT
Ribosome assembly occurs co-transcriptionally on the rRNA genes. This process requires the co-ordinated expression and assembly of many hundreds of proteins and is finely tuned to cell and organism growth. Co-ordinate regulation of the rRNA genes and the ribosomal protein genes is therefore essential for high-fidelity ribosome assembly. Recent work shows that rRNA gene transcription is regulated at the level of elongation via the mitogen-activated protein kinase pathway. We argue that this may provide an explanation for the high fidelity of ribosome assembly.
Subject(s)
RNA, Ribosomal/genetics , Animals , DNA-Directed RNA Polymerases/genetics , Gene Expression Regulation , Growth Substances/physiology , Mammals , Models, Genetic , Models, Molecular , RNA, Ribosomal/chemistry , Transcription, GeneticABSTRACT
Ribosomal transcription in mammals is regulated in response to growth, differentiation, disease, and aging, but the mechanisms of this regulation have remained unresolved. We show that epidermal growth factor induces immediate, ERK1/2-dependent activation of endogenous ribosomal transcription, while inactivation of ERK1/2 causes an equally immediate reversion to the basal transcription level. ERK1/2 was found to phosphorylate the architectural transcription factor UBF at amino acids 117 and 201 within HMG boxes 1 and 2, preventing their interaction with DNA. Mutation of these sites inhibited transcription activation and abrogated the transcriptional response to ERK1/2. Thus, growth factor regulation of ribosomal transcription likely acts by a cyclic modulation of DNA architecture. The data suggest a central role for ribosome biogenesis in growth regulation.