The Nucleolus: In Genome Maintenance and Repair

Tsekrekou, Maria; Stratigi, Kalliopi; Chatzinikolaou, Georgia

doi:10.3390/ijms18071411

Cited by 74 publications

(76 citation statements)

References 158 publications

(182 reference statements)

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“…Accordingly, upon PLK4 inhibition, we detected the formation of RNA:DNA hybrids by immunostaining with the monoclonal antibody S9.6 directed against these structures (Figure 6 A, B). Upon staining fixed cells in situ, the immunofluorescence signal derived from antibody binding was prominent in discrete nuclear structures, compatible with the concept that R-loops mainly occur at specific sites of highly active transcription (Tsekrekou et al, 2017). In contrast, the overexpression of RNaseH1, an RNase that specifically cleaves the RNA component of RNA:DNA hybrids, strongly reduced the nuclear immunostaining signal, confirming the specificity of the antibody (Figure 6 A To clarify the causal link between R-loop formation and replication stress, we performed fiber assays.…”

Section: Centrosome Disintegration Induces Rna:dna Hybrids and This supporting

confidence: 76%

Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

Tayeh

Stegmann

Kleeberg

et al. 2020

Preprint

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Running title: Centrosome integrity supports DNA replicationKey words: Centrosome, CEP152, CCP110, SASS6, CEP152, Polo-like kinase 4 (PLK4), DNA replication, DNA fiber assays, R-loops, MLK3, MK2 alias MAPKAPK2, Seckel syndrome, microcephaly. Highlights:• Centrosome defects cause replication stress independent of mitosis.• MLK3, p38 and MK2 (alias MAPKAPK2) are signalling between centrosome defects and DNA replication stress through R-loop formation. • Patient-derived cells with defective centrosomes display replication stress, whereas inhibition of MK2 restores their DNA replication fork progression and proliferation. ABSTRACT Centrosomes function as organizing centers of microtubules and support accurate mitosis in many animal cells. However, it remains to be explored whether and how centrosomes also facilitate the progression through different phases of the cell cycle. Here we show that impairing the composition of centrosomes, by depletion of centrosomal components or by inhibition of polo-like kinase 4 (PLK4), reduces the progression of DNA replication forks. This occurs even when the cell cycle is arrested before damaging the centrosomes, thus excluding mitotic failure as the source of replication stress. Mechanistically, the kinase MLK3 associates with centrosomes. When centrosomes are disintegrated, MLK3 activates the kinases p38 and MK2/MAPKAPK2. Transcription-dependent RNA:DNA hybrids (R-loops) are then causing DNA replication stress. Fibroblasts from patients with microcephalic primordial dwarfism (Seckel syndrome) harbouring defective centrosomes showed replication stress and diminished proliferation, which were each alleviated by inhibition of MK2. Thus, centrosomes not only facilitate mitosis, but their integrity is also supportive in DNA replication. Graphical abstract MK2 p38 ATF2 JUN Conflict 3 BACKGROUND

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Section: Centrosome Disintegration Induces Rna:dna Hybrids and This supporting

confidence: 76%

Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

Tayeh

Stegmann

Kleeberg

et al. 2020

Preprint

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“…Although separated by the nuclear envelope, nuclear and cytoplasmic RNA granules can share protein components and may communicate [14]. As nuclear bodies have been discussed in detail [12, 15, 16], we focus here on somatic RNA granules in the cytoplasm and their roles in cellular and tissue maintenance.…”

Section: Rna Granules: Location Composition and Size Mattermentioning

confidence: 99%

“…Nucleoli are the most prominent RNA granules in the nucleus; they assemble ribosomes, assist in genome maintenance and facilitate DNA repair. Moreover, nucleoli control stress responses, cell senescence, and apoptosis [12]. Thus, they are indispensable for the maintenance of nucleated somatic cells.…”

Section: Rna Granules: Location Composition and Size Mattermentioning

confidence: 99%

Cytoplasmic RNA Granules in Somatic Maintenance

Moujaber¹,

Stochaj²

2018

Gerontology

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Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent eukaryotes, including yeast, mammals, and plants. The functions of cytoplasmic RNA granules differ widely. They are dictated by the cell type and physiological state, which in turn is determined by intrinsic cell properties and environmental factors. RNA granules provide diverse cellular functions. However, all of the granules contribute to aspects of RNA metabolism. This is exemplified by transcription, RNA storage, silencing, and degradation, as well as mRNP remodeling and regulated translation. Several forms of cytoplasmic mRNA granules are linked to normal physiological processes. For instance, they may coordinate protein synthesis and thereby serve as posttranscriptional “operons”. RNA granules also participate in cytoplasmic mRNA trafficking, a process particularly well understood for neurons. Many forms of RNA granules support the preservation of somatic cell performance under normal and stress conditions. On the other hand, severe insults or disease can cause the formation and persistence of RNA granules that contribute to cellular dysfunction, especially in the nervous system. Neurodegeneration and many other diseases linked to RNA granules are associated with aging. Nevertheless, information related to the impact of aging on the various types of RNA granules is presently very limited. This review concentrates on cytoplasmic RNA granules and their role in somatic cell maintenance. We summarize the current knowledge on different types of RNA granules in the cytoplasm, their assembly and function under normal, stress, or disease conditions. Specifically, we discuss processing bodies, neuronal granules, stress granules, and other less characterized cytoplasmic RNA granules. Our focus is primarily on mammalian and yeast models, because they have been critical to unravel the physiological role of various RNA granules. RNA granules in plants and pathogens are briefly described. We conclude our viewpoint by summarizing the emerging concepts for RNA granule biology and the open questions that need to be addressed in future studies.

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“…In this study, we paid attention to human ribosomal DNA (rDNA) repeat unit, which repeats hundreds of times in diploid human genome. Human rDNA clusters on the short arms of the five acrocentric chromosomes (chromosomes 13,14,15,21,22), and contains a 13-kb transcribed region and a 30-kb intergenic spacer (IGS). Transcribed region encodes 18S, 5.8S and 28S ribosomal RNA.…”

mentioning

confidence: 99%

“…Recently, a study identified 49 conserved regions in IGS through comparative genome in multiple species [14] and revealed the regulation potentials of IGS. rDNA is the fundamental genomic element to form nucleolus where ribosomes assemble together [15,16] and its transcriptional RNA product -ribosomal RNA is indispensable parts of ribosome, which suggests rDNA stability is vital for normal biology processes. Copy number variation of rDNA balances rDNA dosage [17]and is associated with the expression of several functional coherent gene sets [18].…”

mentioning

confidence: 99%

Ribosomal DNA methylation as stable biomarkers for detection of cancer in plasma

Zhang

Fang

Zhang

et al. 2019

Preprint

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BackgroundRecently, liquid biopsy for cancer detection has pursued great progress. However, there are still a lack of high quality markers. It is a challenge to detect cancer stably and accurately in plasma cell free DNA (cfDNA), when the ratio of cancer signal is low. Repetitive genes or elements may improve the robustness of signals. In this study, we focused on ribosomal DNA which repeats hundreds of times in human diploid genome and investigated performances for cancer detection in plasma. ResultsWe collected bisulfite sequencing samples including normal tissues and 4 cancer types and found that intergenic spacer (IGS) of rDNA has high methylation levels and low variation in normal tissues and plasma. Strikingly, IGS of rDNA shows significant hypo-methylation in tumors compared with normal tissues. Further, we collected plasma bisulfite sequencing data from 224 healthy subjects and cancer patients. Means of AUC in testing set were 0.96 (liver cancer), 0.94 (lung cancer and), 0.92 (colon cancer) with classifiers using only 10 CpG sites. Due to the feature of high copy number, when liver cancer plasma WGBS was down-sampled to 10 million raw reads (0.25× whole genome coverage), the prediction performance decreased only a bit (mean AUC=0.93). Finally, methylation of rDNA could also be used for monitor cancer progression and treatment. ConclusionTaken together, we provided the high-resolution map of rDNA methylation in tumors and supported that methylation of rDNA was a competitive and robust marker for detecting cancer and monitoring cancer progression in plasma.

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The Nucleolus: In Genome Maintenance and Repair

Cited by 74 publications

References 158 publications

Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation

Cytoplasmic RNA Granules in Somatic Maintenance

Ribosomal DNA methylation as stable biomarkers for detection of cancer in plasma

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