Over-expression of Hsp83 in grossly depleted hsrω lncRNA background causes synthetic lethality and l(2)gl phenocopy in Drosophila

Ray, Mukulika; Acharya, Sundaram; Shambhavi, Sakshi; Lakhotia, S. C.

doi:10.1007/s12038-019-9852-z

Cited by 16 publications

(25 citation statements)

References 127 publications

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“…The lncRNA hsrω is known to interact with and organize several RBPs like the Drosophila FUS (Cabeza), TDP-43 (TBPH), hnRNPAB (Squid) and hnRNPA2B1 (Hrb87F) to form the ω-speckles, a specialized nuclear compartment that is functionally important; flies that are null for both copies of hsrω exhibit severe dysfunctions in RNA processing and chromatin structure, which causes lethality (Jolly and Lakhotia, 2006; Lakhotia and Sharma, 1996; Lo Piccolo et al, 2017a, 2018; Ray et al, 2019; Ray and Lakhotia, 1998). Together, with such a critical structural role, hsrω also regulates the activity of a large variety of proteins, including the histone acetyltransferase CBP, the chromatin remodeler ISWI and heterochromatin protein 1 (HP1) (Lakhotia et al, 2012; Mallik and Lakhotia, 2010; Onorati et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The lncRNA hsrω regulates arginine dimethylation of human FUS to cause its proteasomal degradation in Drosophila

Piccolo

Mochizuki

Nagai

2019

Journal of Cell Science

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Long non-coding RNAs (lncRNAs) have structural and regulatory effects on RNA-binding proteins (RBPs). However, the mechanisms by which lncRNAs regulate the neurodegenerative-causative RBP like FUS protein remain poorly understood. Here, we show that knockdown of the Drosophila lncRNA hsrω causes a shift in the methylation status of human FUS from mono- (MMA) to di-methylated (DMA) arginine via upregulation of the arginine methyltransferase 5 (PRMT5, known as ART5 in flies). We found this novel regulatory role to be critical for FUS toxicity since the PRMT5-dependent dimethylation of FUS is required for its proteasomal degradation and causes a reduction of high levels of FUS. Moreover, we show that an increase of FUS causes a decline of both PRMT1 (known as ART1 in flies) and PRMT5 transcripts, leading to an accumulation of neurotoxic MMA-FUS. Therefore, overexpression of either PRMT1 or PRMT5 is able to rescue the FUS toxicity. These results highlight a novel role of lncRNAs in post-translation modification (PTM) of FUS and suggest a causal relationship between lncRNAs and dysfunctional PRMTs in the pathogenesis of FUSopathies.

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Section: Introductionmentioning

confidence: 99%

The lncRNA hsrω regulates arginine dimethylation of human FUS to cause its proteasomal degradation in Drosophila

Piccolo

Mochizuki

Nagai

2019

Journal of Cell Science

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“…Given the possible role of hsrω in ITS as seen in this study, earlier report [38] of hsrω 66 mutant larvae phenocopying tumor bearing lgl homozygous larvae, can be viewed in the light of hsrω facilitating survival of cells with loss of lgl, since a substantial down-regulation in expression of lgl was observed in cells with simultaneous loss of hsrω and gain of Hsp83, as seen by Ray et al, [38] sat III a stress-response player in human cancer cells ITS is triggered as an early response to tumor initiation, often resulting in elimination of oncogenic cells at its inception. It is likely that while in relatively simple organism, such as in Drosophila, stress-response gene, hsrω, is co-opted for an ITS function, in the course of evolution, the functional analog of hsrω, the sat III [33], retained its stress-response role and simultaneously diverged to provide a pro-tumorigenic role in mammals.…”

Section: Cell Autonomous Perturbations In Hsrω Affect Multiple Processes Linked To Tumor Progressionmentioning

confidence: 59%

“…Further, in view of inhibition of JNK signaling-triggered cell death by down-regulation of the hsrω transcripts [32], we sought to see if a genetic background of reduced levels of hsrω could promote survival of lgl clones. We generated GFP-marked lgl clones in a heterozygous near null allele of hsrω (hsrω 66 /+) [37,38] genetic background via somatic recombination in early second instar larvae. Unlike the lgl clones generated in hsrω + (wild type) genetic background (Figure 1B), the lgl clones generated in hsrω 66 /+ wing discs survived better, and displayed significant increase in clone size (Figure 2A, B).…”

Section: Its-induced Eliminationmentioning

confidence: 99%

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

Bajpai

Kundu

et al. 2021

Preprint

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Cells incurring oncogenic hits are often eliminated by cell death via built-in anti-cancer defense mechanisms, broadly termed as intrinsic tumor suppression (ITS). Identification of genetic modifiers of ITS-induced cell death would provide better understanding of inherent tumor-resistance and/or susceptibility. Using a Drosophila model of loss of a tumor suppressor-mediated epithelial tumorigenesis, here we show that perturbations in levels of stress-responsive nuclear long non-coding RNA (lncRNA) hsrω gene, promote epithelial tumorigenesis. Thus, while somatic clones with loss of a tumor suppressor, Lgl, are eliminated by JNK-induced cell death, lgl mutant somatic clones induced either in an hsrω loss-of-function heterozygous genetic background, or upon cell autonomous up- or down-regulation of hsrω in lgl somatic clones, override the JNK-mediated cell death and progress to full blown tumors. These tumors display deregulation of Hippo pathway as seen from a gain of downstream target of inhibition, Diap1, an inhibitor of cell death. We finally show that downregulation in sat III non-coding RNA, a functional analog of hsrω in humans, increases sensitivity of cancer cells to cytotoxic stress-induced cell death. lncRNA hsrω, therefore, constitutes a novel genetic modifier of ITS in Drosophila and of stress-induced cell death in human cancers.SummaryA long non-coding RNA, hsrω, is a novel regulator of JNK-mediated intrinsic tumor suppression in Drosophila.Highlightslgl clones induced in hsrω heterozygous loss-of-function genetic background escape intrinsic tumor suppression (ITS).Perturbation of hsrω in lgl mutant clones, too, leads to their escape from ITS.hsrω homeostasis required for JNK-dependent ITS.Human sat III, a functional analog of hsrω, confers stress-resistant to human cancer cells.

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“…The upregulated groups of genes (Table ) in sev‐GAL4 > UAS‐Ras1 V12 hsrω‐RNAi pupae included, among many others, those associated with stress responses, cell and tissue death pathways, autophagy, toll signaling, innate immune system, and so forth. Some of these seem to be primarily due to activated Ras or altered hsrω expression since the Ras/MAPK pathway is known to regulate immune response while the hsrω transcripts have roles in stress responses, cell death, and several other pathways . However, beside the predicted upregulation of G‐protein coupled signal transduction pathway following ectopic expression of activated Ras, a significant increase in expression of several JNK pathway genes was also noted (Tables and ).…”

Section: Resultsmentioning

confidence: 99%

“…Earlier studies in our and other labs have shown that the hsrω lncRNA gene in Drosophila melanogaster regulates many cellular regulatory pathways through diverse mechanisms, of which the modulation of dynamics of heterogeneous nuclear RNA binding proteins (hnRNPs) and certain other RNA binding proteins seems to be a major component . We had earlier found a genetic interaction between Hsp83, Ras signaling pathways and the hsrω lncRNAs .…”

Section: Introductionmentioning

confidence: 89%

Activated Ras/JNK driven Dilp8 in imaginal discs adversely affects organismal homeostasis during early pupal stage in Drosophila, a new checkpoint for development

Ray

Lakhotia

2019

Developmental Dynamics

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Background Dilp8‐mediated inhibition of ecdysone synthesis and pupation in holometabolous insects maintains developmental homeostasis through stringent control of timing and strength of molting signals. We examined reasons for normal pupation but early pupal death observed in certain cases. Results Overexpression of activated Ras in developing eye/wing discs inhibited Ptth expression in brain via upregulated JNK signaling mediated Dilp8 secretion from imaginal discs, which inhibited ecdysone synthesis in prothoracic gland after pupariation, leading to death of ~25‐ to 30‐hour‐old pupae. Inhibition of elevated Ras signaling completely rescued early pupal death while post‐pupation administration of ecdysone to organisms with elevated Ras signaling in eye discs partially rescued their early pupal death. Unlike the earlier known Dilp8 action in delaying pupation, hyperactivated Ras mediated elevation of pJNK signaling in imaginal discs caused Dilp8 secretion after pupariation. Ectopic expression of certain other transgene causing pupal lethality similarly enhanced pJNK and early pupal Dilp8 levels. Suboptimal ecdysone levels after 8 hours of pupation prevented the early pupal metamorphic changes and caused organismal death. Conclusions Our results reveal early pupal stage as a novel Dilp8 mediated post‐pupariation checkpoint and provide further evidence for interorgan signaling during development, wherein a peripheral tissue influences the CNS driven endocrine function.

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Over-expression of Hsp83 in grossly depleted hsrω lncRNA background causes synthetic lethality and l(2)gl phenocopy in Drosophila

Cited by 16 publications

References 127 publications

The lncRNA hsrω regulates arginine dimethylation of human FUS to cause its proteasomal degradation in Drosophila

The lncRNA hsrω regulates arginine dimethylation of human FUS to cause its proteasomal degradation in Drosophila

A Gene Encoding an Architectural RNA,hsrω, is a Host Genetic Modifier of Cancer Progression inDrosophila

Activated Ras/JNK driven Dilp8 in imaginal discs adversely affects organismal homeostasis during early pupal stage in Drosophila, a new checkpoint for development

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