Nucleolus: A Central Hub for Nuclear Functions

Iarovaia, Olga V.; Minina, Elizaveta P.; Sheval, Eugene V.; Onichtchouk, Daria; Dokudovskaya, Svetlana; Razin, Sergey V.; Vassetzky, Yegor S.

doi:10.1016/j.tcb.2019.04.003

Cited by 133 publications

(117 citation statements)

References 149 publications

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“…Some nucleolar proteins, e.g., nucleophosmin, exhibit a nucleolar localization sequence (NoLS) [33]. While there is no highly-conserved NoLS consensus sequence, about half of the amino acids (aa) inside NoLS are lysines and arginines, which render NoLS highly positively charged [23]. Since the nucleolus harbors high numbers of negatively charged RNA molecules, electrostatic interactions between NoLS and RNA molecules were postulated to be responsible for nucleolar accumulation of NoLS-bearing proteins.…”

Section: How Do Nucleoli Respond To Stress and Dna Damage?mentioning

confidence: 99%

“…This led to the assumption that the nucleolus has non-canonical regulatory functions beyond ribosome biogenesis. At present, it is well accepted that the nucleolus is a multifunctional nuclear sub-compartment, with additional roles, e.g., in stress response, DNA damage signaling, telomere maintenance, cell cycle control, cell proliferation, and proteostasis [23]. Furthermore, links between nucleolar functions and complex physiological and pathophysiological cellular processes have been established.…”

Section: Introduction Into the Biology Of Nucleolimentioning

confidence: 99%

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The Nucleolus and PARP1 in Cancer Biology

Engbrecht¹,

Mangerich²

2020

Cancers

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The nucleolus has been known for a long time to fulfill crucial functions in ribosome biogenesis, of which cancer cells can become addicted to in order to produce sufficient amounts of proteins for cell proliferation. Recently, the nucleolus has emerged as a central regulatory hub in many other cancer-relevant processes, including stress sensing, DNA damage response, cell cycle control, and proteostasis. This fostered the idea that nucleolar processes can be exploited in cancer therapy. Interestingly, a significant proportion of poly(ADP-ribose) polymerase 1 (PARP1) molecules are localized in the nucleolus and PARP1 also plays crucial roles in many processes that are important in cancer biology, including genome maintenance, replication, transcription, and chromatin remodeling. Furthermore, during the last years, PARP1 came into focus in oncology since it represents a promising target of pharmacological PARP inhibitors in various types of cancers. Here, we provide an overview of our current understanding on the role of PARP1 in nucleolar functions and discuss potential implications in cancer biology and therapy.

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Section: How Do Nucleoli Respond To Stress and Dna Damage?mentioning

confidence: 99%

Section: Introduction Into the Biology Of Nucleolimentioning

confidence: 99%

The Nucleolus and PARP1 in Cancer Biology

Engbrecht¹,

Mangerich²

2020

Cancers

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“…EXOSC3 is part of the RNA exosome complex; it possesses 3' to 5' exoribonuclease activity and it is involved in eliminating transcriptional byproducts. Known substrates include non-coding transcripts, such as promoter-upstream transcripts (PROMPTs), mRNAs with processing defects [46,47] and most prominently rRNA and snoRNAs, as part of their normal processing and maturation in the nucleolus [48] . The EXOSC3 knockdown had little or no effect on transcripts of protein-coding genes and their associated DoGs and LoGs; however, there is a marked effect on the stability of lncRNAs, UoGs and independent TUs in the nucleoplasmic fraction ( Figure 5B and S5B).…”

Section: Rapid Degradation Of Chromatin-associated Intergenic Rnasmentioning

confidence: 99%

Intergenic RNA mainly derives from nascent transcripts of known genes

Federico

Zagalak

Attig

et al. 2020

Preprint

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Background: Eukaryotic genomes undergo pervasive transcription, leading to the production of many types of stable and unstable RNAs. Transcription is not restricted to regions with annotated gene features but includes almost any genomic context. Currently, the source and function of most RNAs originating from intergenic regions in the human genome remains unclear. Results: We hypothesised that many intergenic RNA can be ascribed to the presence of as-yet unannotated genes or the 'fuzzy' transcription of known genes that extends beyond the annotated boundaries. To elucidate the contributions of these two sources, we assembled a dataset of >2.5 billion publicly available RNA-seq reads across 5 human cell lines and multiple cellular compartments to annotate transcriptional units in the human genome. About 80% of transcripts from unannotated intergenic regions can be attributed to the fuzzy transcription of existing genes; the remaining transcripts originate mainly from putative long non-coding RNA loci that are rarely spliced. We validated the transcriptional activity of these intergenic RNA using independent measurements, including transcriptional start sites, chromatin signatures, and genomic occupancies of RNA polymerase II in various phosphorylation states. We also analysed the nuclear localisation and sensitivities of intergenic transcripts to nucleases to illustrate that they tend to be rapidly degraded either by the exosome. Conclusions: We provide a curated atlas of intergenic RNAs that distinguishes between alternative processing of well annotated genes from independent transcriptional units based on the combined analysis of chromatin signatures, nuclear RNA localisation and degradation pathways.

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“…In addition, membrane-less organelles that result from biomolecular condensation have been described (6)(7)(8)(9). In the nucleus they include the nucleolus (10,11), nuclear speckles (12,13), and cajal bodies (14)(15)(16); stress granules (2,17,18), germ granules (19,20), and processing bodies (21,22) have been found in the cytoplasm. The formation of such condensates depends on the composition and concentration of biomolecules (9) as well as environmental conditions such as pH, temperature, and the concentration of ions (6,23,24).…”

Section: Introductionmentioning

confidence: 99%

Charge-Driven Condensation of RNA and Proteins Suggests Broad Role of Phase Separation in Cytoplasmic Environments

Dutagaci

Nawrocki

Goodluck

et al. 2020

Preprint

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Phase separation of globular RNA and positively charged proteins is reported from a combination of coarse-grained simulations parametrized based on atomistic simulations, theory informed by the coarse-grained simulations, and experimental validation via confocal microscopy and FRET spectroscopy. Phase separation is found to depend on concentration, size, and charge of the proteins, requiring a minimum protein size, minimum protein charge, and minimum protein concentration before condensates can form. The general principle for phase separation is based on electrostatic complementarity rather than invoking polymer character as in most previous studies. Simulation results furthermore suggest that such phase separation may occur in heterogenous cellular environment, not just between tRNA and cellular proteins but also between ribosomes and proteins where there may be competition for positively charged proteins. STATEMENT OF SIGNIFICANCELiquid-liquid phase separation has been recognized as a key mechanism for forming membraneless organelles in cells. Commonly discussed mechanisms invoke a role of disordered peptides and specific multi-valent interactions. We report here phase separation of RNA and proteins based on a more universal principle of charge complementarity that does not require disorder or specific interactions. The findings are supported by coarse-grained simulations, theory, and experimental validation via microscopy and FRET spectroscopy. The implications of this work are that condensate formation may be an even more universal phenomenon in biological systems than thought to date.

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Nucleolus: A Central Hub for Nuclear Functions

Cited by 133 publications

References 149 publications

The Nucleolus and PARP1 in Cancer Biology

The Nucleolus and PARP1 in Cancer Biology

Intergenic RNA mainly derives from nascent transcripts of known genes

Charge-Driven Condensation of RNA and Proteins Suggests Broad Role of Phase Separation in Cytoplasmic Environments

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