scholarly journals Genetic compensation is triggered by mutant mRNA degradation

2018 ◽  
Author(s):  
Mohamed A. El-Brolosy ◽  
Andrea Rossi ◽  
Zacharias Kontarakis ◽  
Carsten Kuenne ◽  
Stefan Günther ◽  
...  
Keyword(s):  
Protein Function ◽  
Mrna Decay ◽  
Degradation Products ◽  
Sequence Similarity ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Genetic Compensation

Genetic compensation by transcriptional modulation of related gene(s) (also known as transcriptional adaptation) has been reported in numerous systems1–3; however, whether and how such a response can be activated in the absence of protein feedback loops is unknown. Here, we develop and analyze several models of transcriptional adaptation in zebrafish and mouse that we show are not caused by loss of protein function. We find that the increase in transcript levels is due to enhanced transcription, and observe a correlation between the levels of mutant mRNA decay and transcriptional upregulation of related genes. To assess the role of mutant mRNA degradation in triggering transcriptional adaptation, we use genetic and pharmacological approaches and find that mRNA degradation is indeed required for this process. Notably, uncapped RNAs, themselves subjected to rapid degradation, can also induce transcriptional adaptation. Next, we generate alleles that fail to transcribe the mutated gene and find that they do not show transcriptional adaptation, and exhibit more severe phenotypes than those observed in alleles displaying mutant mRNA decay. Transcriptome analysis of these different alleles reveals the upregulation of hundreds of genes with enrichment for those showing sequence similarity with the mutated gene’s mRNA, suggesting a model whereby mRNA degradation products induce the response via sequence similarity. These results expand the role of the mRNA surveillance machinery in buffering against mutations by triggering the transcriptional upregulation of related genes. Besides implications for our understanding of disease-causing mutations, our findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.

scholarly journals Transcriptional adaptation: a mechanism underlying genetic robustness

Development ◽  
2020 ◽  
Vol 147 (15) ◽  
pp. dev186452 ◽  
Author(s):  
Tamar E. Sztal ◽  
Didier Y. R. Stainier
Keyword(s):  
Genetic Variation ◽  
Protein Function ◽  
Regulatory Elements ◽  
Mrna Degradation ◽  
Coding Regions ◽  
Genetic Robustness ◽  
Genetic Perturbations ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Upregulated Genes

ABSTRACTMutations play a crucial role in evolution as they provide the genetic variation that allows evolutionary change. Although some mutations in regulatory elements or coding regions can be beneficial, a large number of them disrupt gene function and reduce fitness. Organisms utilize several mechanisms to compensate for the damaging consequences of genetic perturbations. One such mechanism is the recently identified process of transcriptional adaptation (TA): during this event, mutations that cause mutant mRNA degradation trigger the transcriptional modulation of so-called adapting genes. In some cases, for example when one (or more) of the upregulated genes is functionally redundant with the mutated gene, this process compensates for the loss of the mutated gene's product. Notably, unlike other mechanisms underlying genetic robustness, TA is not triggered by the loss of protein function, an observation that has prompted studies into the machinery of TA and the contexts in which it functions. Here, we review the discovery and current understanding of TA, and discuss how its main features appear to be conserved across species. In light of these findings, we also speculate on the importance of TA in the context of human disease, and provide some recommendations for genome-editing strategies that should be more effective.

scholarly journals CLK-2/TEL2 is a conserved component of the nonsense-mediated mRNA decay pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244505
Author(s):  
Yanwu Guo ◽  
Cristina Tocchini ◽  
Rafal Ciosk
Keyword(s):  
Mrna Decay ◽  
Forward Genetics ◽  
Morphological Effect ◽  
Dna Damage Signaling ◽  
Mrna Surveillance ◽  
Genetic Landscape ◽  
Nonsense Mediated Mrna Decay ◽  
Novel Strategy ◽  
Conserved Gene

Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.

When mRNA translation meets decay

2017 ◽  
Vol 45 (2) ◽  
pp. 339-351 ◽  
Author(s):  
Alicia A. Bicknell ◽  
Emiliano P. Ricci
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Protein Output

Messenger RNA (mRNA) translation and mRNA degradation are important determinants of protein output, and they are interconnected. Previously, it was thought that translation of an mRNA, as a rule, prevents its degradation. mRNA surveillance mechanisms, which degrade mRNAs as a consequence of their translation, were considered to be exceptions to this rule. Recently, however, it has become clear that many mRNAs are degraded co-translationally, and it has emerged that codon choice, by influencing the rate of ribosome elongation, affects the rate of mRNA decay. In this review, we discuss the links between translation and mRNA stability, with an emphasis on emerging data suggesting that codon optimality may regulate mRNA degradation.

scholarly journals Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

2021 ◽  
Author(s):  
Yuichiro Mishima ◽  
Peixun Han ◽  
Seisuke Kimura ◽  
Shintaro Iwasaki
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Expression Patterns ◽  
Mrna Degradation ◽  
Zebrafish Embryos ◽  
Reading Frame ◽  
Genome Wide ◽  
Codon Composition ◽  
Kinetics Of

The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame (ORF) determines mRNA stability in multiple organisms. Based on genome-wide correlation approaches, this previously unrecognized role of the genetic code is attributable to the kinetics of the codon-decoding process by the ribosome. However, complementary experimental analysis is required to define the codon effects on mRNA stability apart from the related cotranslational mRNA decay pathways such as those triggered by aberrant ribosome stalls. In the current study, we performed a set of reporter-based analyses to define codon-mediated mRNA decay and ribosome stall-dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of Znf598 and stall-dependent mRNA decay. We propose that codon-mediated mRNA decay is triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

scholarly journals SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Volker Boehm ◽  
Sabrina Kueckelmann ◽  
Jennifer V. Gerbracht ◽  
Sebastian Kallabis ◽  
Thiago Britto-Borges ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Translation Termination ◽  
Mrna Degradation ◽  
Functional Connection ◽  
Eukaryotic Gene Expression ◽  
Eukaryotic Gene ◽  
Nonsense Mediated Mrna Decay ◽  
Improved Model ◽  
Dependent Pathway

AbstractEukaryotic gene expression is constantly controlled by the translation-coupled nonsense-mediated mRNA decay (NMD) pathway. Aberrant translation termination leads to NMD activation, resulting in phosphorylation of the central NMD factor UPF1 and robust clearance of NMD targets via two seemingly independent and redundant mRNA degradation branches. Here, we uncover that the loss of the first SMG5-SMG7-dependent pathway also inactivates the second SMG6-dependent branch, indicating an unexpected functional connection between the final NMD steps. Transcriptome-wide analyses of SMG5-SMG7-depleted cells confirm exhaustive NMD inhibition resulting in massive transcriptomic alterations. Intriguingly, we find that the functionally underestimated SMG5 can substitute the role of SMG7 and individually activate NMD. Furthermore, the presence of either SMG5 or SMG7 is sufficient to support SMG6-mediated endonucleolysis of NMD targets. Our data support an improved model for NMD execution that features two-factor authentication involving UPF1 phosphorylation and SMG5-SMG7 recruitment to access SMG6 activity.

Genotype–Phenotype Relationships in the Context of Transcriptional Adaptation and Genetic Robustness

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Gabrielius Jakutis ◽  
Didier Y.R. Stainier
Keyword(s):  
Genome Engineering ◽  
Annual Review ◽  
Publication Date ◽  
Genetic Manipulations ◽  
Functional Studies ◽  
Genetic Robustness ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Additional Explanation

Genetic manipulations with a robust and predictable outcome are critical to investigate gene function, as well as for therapeutic genome engineering. For many years, knockdown approaches and reagents including RNA interference and antisense oligonucleotides dominated functional studies; however, with the advent of precise genome editing technologies, CRISPR-based knockout systems have become the state-of-the-art tools for such studies. These technologies have helped decipher the role of thousands of genes in development and disease. Their use has also revealed how limited our understanding of genotype–phenotype relationships is. The recent discovery that certain mutations can trigger the transcriptional modulation of other genes, a phenomenon called transcriptional adaptation, has provided an additional explanation for the contradicting phenotypes observed in knockdown versus knockout models and increased awareness about the use of each of these approaches. In this review, we first cover the strengths and limitations of different gene perturbation strategies. Then we highlight the diverse ways in which the genotype–phenotype relationship can be discordant between these different strategies. Finally, we review the genetic robustness mechanisms that can lead to such discrepancies, paying special attention to the recently discovered phenomenon of transcriptional adaptation. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Transcriptional adaptation in Caenorhabditis elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Vahan Serobyan ◽  
Zacharias Kontarakis ◽  
Mohamed A El-Brolosy ◽  
Jordan M Welker ◽  
Oleg Tolstenkov ◽  
...  
Keyword(s):  
Small Rna ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Mouse Cell ◽  
C Elegans ◽  
Argonaute Proteins ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Rna Maturation

Transcriptional adaptation is a recently described phenomenon by which a mutation in one gene leads to the transcriptional modulation of related genes, termed adapting genes. At the molecular level, it has been proposed that the mutant mRNA, rather than the loss of protein function, activates this response. While several examples of transcriptional adaptation have been reported in zebrafish embryos and in mouse cell lines, it is not known whether this phenomenon is observed across metazoans. Here we report transcriptional adaptation in C. elegans, and find that this process requires factors involved in mutant mRNA decay, as in zebrafish and mouse. We further uncover a requirement for Argonaute proteins and Dicer, factors involved in small RNA maturation and transport into the nucleus. Altogether, these results provide evidence for transcriptional adaptation in C. elegans, a powerful model to further investigate underlying molecular mechanisms.

The Leukocyte Digestion of Fibrinogen Degradation Products (FDP)

1971 ◽  
Vol 26 (03) ◽  
pp. 523-525
Author(s):  
K Gibiński ◽  
B Lipiński ◽  
M Trusz-Gluza
Keyword(s):  
Degradation Products ◽  
Fibrinogen Degradation Products

SummaryWhile the native fibrinogen is not digested by the leucocyte proteases both the early and late FDP are digestible without any denaturating reagent. Thus, this reaction may occur in vivo indicating an unknown role of granulocytes in paracoagulation.

Exercise-Induced Fibrinolysis – Fact or Fiction?

1982 ◽  
Vol 48 (02) ◽  
pp. 201-203 ◽  
Author(s):  
N A Marsh ◽  
P J Gaffney
Keyword(s):  
Plasminogen Activator ◽  
Degradation Products ◽  
Coagulation Factors ◽  
Vascular Wall ◽  
Strenuous Exercise ◽  
Fibrin Degradation Products ◽  
Real Increase ◽  
Exercise Induced ◽  
Male Subjects

SummaryThe effect of strenuous exercise on the fibrinolytic and coagulation mechanisms was examined in six healthy male subjects. Five min bicycle exercise at a work-rate of 800 to 1200 kpm. min−1 produced an abrupt increase in plasma plasminogen activator levels which disappeared after 90 min. However, there was no change in early or late fibrin degradation products nor was there a change in fibrinopeptide A levels or βthromboglobulin levels after exercise although activated partial thromboplastin times were significantly shortened. It is concluded that strenuous exercise does not produce any real increase in fibrinogen-fibrin conversion nor any real increase in the breakdown of these proteins. The role of exercise-induced release of plasminogen activator remains unclear, but probably helps to maintain plasma levels in a discontinuous manner concurrently with the continuous low-level secretion from the vascular wall. The shortening of partial thromboplastin time may be due to the raised levels of plasminogen activator changing the activation state of other coagulation factors.

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