RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

Laffleur, Brice; Basu, Uttiya; Lim, Jung Hyun

doi:10.1016/j.jmb.2016.12.021

Cited by 15 publications

(15 citation statements)

References 124 publications

(123 reference statements)

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“…Over the last decade, the concept has emerged that exosome-mediated R-loop prevention is a critical step in immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes [ 171 ]. To initiate CSR and SHM, activation-induced cytidine deaminase (AID) deaminates cytidines on both template and non-template DNA strands of transcribing switch regions.…”

Section: Significance Of the Nuclear Rna Exosome In Mammalian Biolmentioning

confidence: 99%

RNA Surveillance by the Nuclear RNA Exosome: Mechanisms and Significance

Ogami

Chen

Manley

2018

ncRNA

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The nuclear RNA exosome is an essential and versatile machinery that regulates maturation and degradation of a huge plethora of RNA species. The past two decades have witnessed remarkable progress in understanding the whole picture of its RNA substrates and the structural basis of its functions. In addition to the exosome itself, recent studies focusing on associated co-factors have been elucidating how the exosome is directed towards specific substrates. Moreover, it has been gradually realized that loss-of-function of exosome subunits affect multiple biological processes such as the DNA damage response, R-loop resolution, maintenance of genome integrity, RNA export, translation and cell differentiation. In this review, we summarize the current knowledge of the mechanisms of nuclear exosome-mediated RNA metabolism and discuss their physiological significance.

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Section: Significance Of the Nuclear Rna Exosome In Mammalian Biolmentioning

confidence: 99%

RNA Surveillance by the Nuclear RNA Exosome: Mechanisms and Significance

Ogami

Chen

Manley

2018

ncRNA

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“…10,11 As the main information molecules in exosomes, non-coding RNAs are primary mediators of the functions of exosomes. 12 However, the role of chondrosarcoma cell-derived exosomes in the progression of chondrosarcoma remains unelucidated.…”

Section: Introductionmentioning

confidence: 99%

<p>Exosomal lncRNA RAMP2-AS1 Derived from Chondrosarcoma Cells Promotes Angiogenesis Through miR-2355-5p/VEGFR2 Axis</p>

Cheng¹,

Zhang²,

Cheng³

et al. 2020

OTT

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Objective: Exosomes derived from cancer cells can alter the microenvironment and enhance cancer malignancy through the regulation of peripheral cell functions. The present study focused on the crosstalk between chondrosarcoma cells and human umbilical vein endothelial cells (HUVECs) mediated by exosomes derived from chondrosarcoma cells and aimed to explore the potential molecular mechanism. Materials and Methods: Chondrosarcoma cell-derived exosomes were isolated and characterized. Cell proliferation assay, tube formation assay and transwell migration assay were performed to characterize the effects of exosomes on HUVECs. The lncRNA microarray was used to select differentially expressed lncRNAs in HUVECs treated with or without exosomes. Serum samples of patients with chondrosarcoma were collected to analyze the correlation between the RAMP2-AS1 level and the clinicopathological features. Online databases were used to predict the target microRNA of RAMP2-AS1. Dual luciferase reporter assay, Western blotting and qRT-PCR assays were performed to verify the interactions among RAMP2-AS1, miR-2355-5p and VEGFR2. Rescue experiments were conducted to validate the existence of the RAMP2-AS1/miR-2355-5p/VEGFR2 axis. Results: The exosomes secreted by chondrosarcoma cells could enhance HUVECs proliferation, migration and tube formation. LncRNA microarray analysis revealed that exosomes carried lncRNA RAMP2-AS1, and further verification showed that the level of RAMP2-AS1 was increased in the serum of chondrosarcoma patients and was closely related to local invasiveness, distant metastasis and poor prognosis. Subsequent experiments demonstrated that RAMP2-AS1 knockdown could partly abrogate the promoting effects on angiogenesis induced by exosomes derived from chondrosarcoma cells. Moreover, dual luciferase reporter assay and rescue experiments suggested that the RAMP2-AS1/miR-2355-5p/VEGFR2 axis was responsible for exosome-induced angiogenesis of HUVECs. Conclusion: Chondrosarcoma cell-derived exosomes carry lncRNA RAMP2-AS1, which acts as a ceRNA of miR-2355-5p to regulate VEGFR2 expression, thereby positively regulating the angiogenic ability of HUVECs. Thus, exosomal RAMP2-AS1 has the potential as a novel biomarker and therapeutic target for chondrosarcoma.

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“…It has been reported that the elongation-competent RNA polymerase II complex, when transcriptionally stalled at the IgH switch sequence (IgS), recruits AID using the RNA processing activity of the 3 0 -5 0 noncoding RNA exonuclease RNA exosome complex (Basu et al, 2011;Pavri et al, 2010;Pavri and Nussenzweig, 2011;Rajagopal et al, 2009;Wang et al, 2009). AID and RNA exosome directly interact with each other, providing evidence for ncRNA-processing-mediated targeting of AID to its physiological DNA substrates (Basu et al, 2011;Chandra et al, 2015;Laffleur et al, 2017). Another observation is the role of RNA exosome in providing AID access to the template DNA of the IgS (switch) regions.…”

Section: Introductionmentioning

confidence: 99%

Effects of senataxin and RNA exosome on B-cell chromosomal integrity

Kazadi

Lim

Rothschild

et al. 2020

Heliyon

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Loss of function of senataxin (SETX), a bona-fide RNA/DNA helicase, is associated with neuronal degeneration leading to Ataxia and Ocular Apraxia (AOA) in human patients. SETX is proposed to promote transcription termination, DNA replication, DNA repair, and to unwind deleterious RNA:DNA hybrids in the genome. In all the above-mentioned mechanisms, SETX unwinds transcription complex-associated nascent RNA which is then degraded by the RNA exosome complex. Here we have used B cells isolated from a SETX mutant mouse model and compared genomic instability and immunoglobulin heavy chain locus (IgH) class switch recombination (CSR) to evaluate aberrant and programmed genomic rearrangements, respectively. Similar to RNA exosome mutant primary B cells, SETX mutant primary B cells display genomic instability but a modest decrease in efficiency of CSR. Furthermore, knockdown of Setx mRNAs from CH12-F3 B-cell lines leads to a defect in IgA CSR and accumulation of aberrant patterns of mutations in IgH switch sequences. Given that SETX mutant mice do not recapitulate the AOA neurodegenerative phenotype, it is possible that some aspects of SETX biology are rescued by redundant helicases in mice. Overall, our study provides new insights into the role of the SETX/RNA exosome axis in suppressing genomic instability so that programmed DNA breaks are properly orchestrated.

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RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

Cited by 15 publications

References 124 publications

RNA Surveillance by the Nuclear RNA Exosome: Mechanisms and Significance

RNA Surveillance by the Nuclear RNA Exosome: Mechanisms and Significance

<p>Exosomal lncRNA RAMP2-AS1 Derived from Chondrosarcoma Cells Promotes Angiogenesis Through miR-2355-5p/VEGFR2 Axis</p>

Effects of senataxin and RNA exosome on B-cell chromosomal integrity

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