Novel nucleolar pathway connecting intracellular energy status with p53 activation.
ABSTRACT In response to a shortage of intracellular energy, mammalian cells reduce energy consumption and induce cell cycle arrest, both of which contribute to cell survival. Here we report that a novel nucleolar pathway involving the energy-dependent nucleolar silencing complex (eNoSC) and Myb-binding protein 1a (MYBBP1A) is implicated in these processes. Namely, in response to glucose starvation, eNoSC suppresses rRNA transcription, which results in a reduction in nucleolar RNA content. As a consequence, MYBBP1A, which is anchored to the nucleolus via RNA, translocates from the nucleolus to the nucleoplasm. The translocated MYBBP1A induces acetylation and accumulation of p53 by enhancing the interaction between p300 and p53, which eventually leads to the cell cycle arrest (or apoptosis). Taken together, our results indicate that the nucleolus works as a sensor that transduces the intracellular energy status into the cell cycle machinery.
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ABSTRACT: At its broadest sense, to say that a phenotype is epigenetic suggests that it occurs without changes in DNA sequence, yet is heritable through cell division and occasionally from one organismal generation to the next. Since gene regulatory changes are oftentimes in response to environmental stimuli and may be retained in descendent cells, there is a growing expectation that one's experiences may have consequence for subsequent generations and thus impact evolution by decoupling a selectable phenotype from its underlying heritable genotype. But the risk of this overbroad use of "epigenetic" is a conflation of genuine cases of heritable non-sequence genetic information with trivial modes of gene regulation. A look at the term "epigenetic" and some problems with its increasing prevalence argues for a more reserved and precise set of defining characteristics. Additionally, questions arising about how we define the "sequence independence" aspect of epigenetic inheritance suggest a form of genome evolution resulting from induced polymorphisms at repeated loci (e.g., the rDNA or heterochromatin).01/2012; 2012:867951. DOI:10.1155/2012/867951
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ABSTRACT: Transcription of the ribosomal RNA gene repeats by Pol I occurs in the nucleolus and is a fundamental step in ribosome biogenesis and protein translation. Due to tight coordination between ribosome biogenesis and cell proliferation, transcription of rRNA and stable maintenance of rDNA clusters are thought to be under intricate control by intercalated mechanisms, particularly at the epigenetic level. Here we identify the nucleolar protein Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of rRNA expression. Suppression of rDNA transcription by Mybbp1a was linked to promoter regulation as illustrated by its binding to the chromatin around the hypermethylated, inactive rDNA gene promoters. Our data further showed that downregulation of Mybbp1a abrogated the local DNA methylation levels and histone marks associated with gene silencing, and altered the promoter occupancy of various factors such UBF and HDACs, consequently leading to elevated rRNA expression. Mechanistically, we propose that Mybbp1a maintains rDNA repeats in a silenced state while in association with the negative epigenetic modifiers HDAC1/2. Results from our present work reveal a previously unrecognized co-repressor role of Mybbp1a in rRNA expression. They are further consistent with the scenario that Mybbp1a is an integral constituent of the rDNA epigenetic regulation that underlies the balanced state of rDNA clusters.Journal of Biomedical Science 06/2012; 19(1):57. DOI:10.1186/1423-0127-19-57 · 2.74 Impact Factor
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ABSTRACT: Within the nucleus, the nucleolus is a dynamic compartment which is critical to maintain cellular homeostasis under normal, stress and disease conditions. During the last years, proteomics research provided new information on the complexity of nucleolar proteomes. These studies also established that many chaperones, co-chaperones and other factors involved in proteostasis associate with nucleoli in the absence of stress or disease. Moreover, quantitative proteomics demonstrated that physiological and environmental changes alter the nucleolar profile of chaperones and co-chaperones. At present, the emphasis has shifted towards sophisticated in-depth analyses of the nucleolar proteome. As such, turnover and posttranslational modifications are now quantified for individual proteins that associate with nucleoli. This large body of work generated new insights into the sumoylation, phosphorylation and acetylation of the nucleolar proteome. At the same time, we have gained a better understanding of the nucleolar organization, as novel subcompartments were identi-fied within the nucleolus that are induced by physiological and other forms of stress. Notably, some of these subcompart-ments are also enriched for chaperones. To review these results, we will focus on recent studies that analyzed the nucleo-lar proteome, and particular emphasis will be given to nucleolar chaperones. Despite remarkable progress in the field, cru-cial questions regarding the physiological relevance of nucleolar chaperones remain to be answered in the years ahead. We conclude our update by discussing these future directions in the context of the latest developments in the nucleolar and chaperone fields.