scholarly journals The 3'UTR of the orb2 gene encoding the Drosophila CPEB translation factor plays a critical role in spermatogenesis

Development ◽  
2021 ◽  
Author(s):  
Rudolf A. Gilmutdinov ◽  
Eugene N. Kozlov ◽  
Konstantin V. Yakovlev ◽  
Ludmila V. Olenina ◽  
Alexei A. Kotov ◽  
...  
Keyword(s):  
Critical Role ◽  
Biological Processes ◽  
Apparent Effect ◽  
Gene Encoding ◽  
Translation Factor ◽  
Initial Polarization

CPEB proteins are conserved translation regulators involved in multiple biological processes. One of these proteins in Drosophila, Orb2, is a principal player in spermatogenesis. It is required for meiosis and spermatid differentiation. During the later process orb2 mRNAs and proteins are localized within the developing spermatid. To evaluate the role of orb2 mRNA 3'UTR in spermatogenesis, we used the CRISPR/Cas9 system to generate a deletion of the orb2 3'UTR, orb2R. This deletion disrupts the process of spermatid differentiation but has no apparent effect on meiosis. Differentiation abnormalities include defects in the initial polarization of the 64-cell spermatid cysts, mislocalization of mRNAs and proteins in the elongating spermatid tails, altered morphology of the elongating spermatid tails, and defects in the assembly of the individualization complex. These disruptions in differentiation appear to arise because orb2 mRNAs and proteins are not properly localized within the 64-cell spermatid cyst.

scholarly journals The 3’UTR of the orb2 gene encoding the Drosophila CPEB translation factor plays a critical role in spermatogenesis

2020 ◽  
Author(s):  
Rudolf A. Gilmutdinov ◽  
Eugene N. Kozlov ◽  
Ludmila V. Olenina ◽  
Alexei A. Kotov ◽  
Justinn Barr ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Critical Role ◽  
Self Regulation ◽  
Biological Processes ◽  
Apparent Effect ◽  
Gene Encoding ◽  
Cytoplasmic Polyadenylation ◽  
Polarized Cells ◽  
Biological Context

AbstractCPEB proteins are conserved translation regulators involved in multiple biological processes. One of these proteins in Drosophila, Orb2, is a principal player in spermatogenesis. It is required for meiosis and spermatid differentiation. During the later process orb2 mRNAs and proteins are localized within the developing spermatid. To evaluate the role of orb2 mRNA 3’UTR in spermatogenesis, we used the CRISPR/Cas9 system to generate a deletion of the orb2 3’UTR, orb2R. This deletion disrupts the process of spermatid differentiation, but has no apparent effect on meiosis. While this deletion appears to destabilize the orb2 mRNA and reduce the levels of Orb2 protein, this is not the primary cause of the differentiation defects. Instead, differentiation appears to be disrupted because orb2 mRNAs and proteins are not properly localized within the differentiating spermatids. Other transcripts and proteins involved in spermatogenesis are also mislocalized in orb2R spermatids.Author summaryThe conserved family of cytoplasmic polyadenylation element binding (CPEB) proteins can activate or repress translation of target mRNAs, depending on the specific biological context, through interaction with special cytoplasmic polyadenylation element (CPE) sequences. These proteins function mainly in highly polarized cells. Orb2, one of the two Drosophila melanogaster CPEB proteins, is predominantly expressed in the testes and is crucial for spermatogenesis. The 3’UTR of orb2 transcript contains multiple CPE-like motifs, which is indicative of orb2 self-regulation. We have generated a deletion that removes the greater portion of 3’UTR. While this deletion causes a reduction in the levels of orb2 mRNA and the protein, this does not appear to be responsible for the defects in spermatogenesis observed in the deletion mutant. Instead, it is the mislocalization of the mRNA and protein in the developing spermatids.

scholarly journals CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130217 ◽  
Author(s):  
Puneet Sharma ◽  
Alo Nag
Keyword(s):  
Ubiquitin Ligase ◽  
Drug Target ◽  
Critical Role ◽  
Cellular Transformation ◽  
Biological Processes ◽  
Molecular Architecture ◽  
The Past ◽  
Cullin 4A ◽  
Broad Overview

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.

scholarly journals Molecular characterization and clinical relevance of m6A regulators across 33 cancer types

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yongsheng Li ◽  
Jun Xiao ◽  
Jing Bai ◽  
Yi Tian ◽  
Yinwei Qu ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Critical Role ◽  
Genetic Alterations ◽  
Biological Processes ◽  
Valuable Resource ◽  
Multiple Cancer ◽  
Molecular Alterations ◽  
Prognostic Stratification ◽  
Cancer Types

Abstract The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer.

scholarly journals Sinorhizobium meliloti Requires a Cobalamin-Dependent Ribonucleotide Reductase for Symbiosis With Its Plant Host

2010 ◽  
Vol 23 (12) ◽  
pp. 1643-1654 ◽  
Author(s):  
Michiko E. Taga ◽  
Graham C. Walker
Keyword(s):  
Ribonucleotide Reductase ◽  
Sinorhizobium Meliloti ◽  
Critical Role ◽  
Methionine Synthase ◽  
Nitrogen Fixing ◽  
Plant Host ◽  
Gene Encoding ◽  
Cobalamin Biosynthesis ◽  
Methionine Synthesis

Vitamin B12 (cobalamin) is a critical cofactor for animals and protists, yet its biosynthesis is limited to prokaryotes. We previously showed that the symbiotic nitrogen-fixing alphaproteobacterium Sinorhizobium meliloti requires cobalamin to establish a symbiotic relationship with its plant host, Medicago sativa (alfalfa). Here, the specific requirement for cobalamin in the S. meliloti–alfalfa symbiosis was investigated. Of the three known cobalamin-dependent enzymes in S. meliloti, the methylmalonyl CoA mutase (BhbA) does not affect symbiosis, whereas disruption of the metH gene encoding the cobalamin-dependent methionine synthase causes a significant defect in symbiosis. Expression of the cobalamin-independent methionine synthase MetE alleviates this symbiotic defect, indicating that the requirement for methionine synthesis does not reflect a need for the cobalamin-dependent enzyme. To investigate the function of the cobalamin-dependent ribonucleotide reductase (RNR) encoded by nrdJ, S. meliloti was engineered to express an Escherichia coli cobalamin-independent (class Ia) RNR instead of nrdJ. This strain is severely defective in symbiosis. Electron micrographs show that these cells can penetrate alfalfa nodules but are unable to differentiate into nitrogen-fixing bacteroids and, instead, are lysed in the plant cytoplasm. Flow cytometry analysis indicates that these bacteria are largely unable to undergo endoreduplication. These phenotypes may be due either to the inactivation of the class Ia RNR by reactive oxygen species, inadequate oxygen availability in the nodule, or both. These results show that the critical role of the cobalamin-dependent RNR for survival of S. meliloti in its plant host can account for the considerable resources that S. meliloti dedicates to cobalamin biosynthesis.

scholarly journals An Update on the Role of Ubiquitination in Melanoma Development and Therapies

2021 ◽  
Vol 10 (5) ◽  
pp. 1133
Author(s):  
Frédéric Soysouvanh ◽  
Serena Giuliano ◽  
Nadia Habel ◽  
Najla El-Hachem ◽  
Céline Pisibon ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Biological Processes ◽  
Large Array ◽  
Skin Cancers ◽  
Melanoma Patients ◽  
Ubiquitination System ◽  
Pleiotropic Functions

The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

scholarly journals p53 Family: Role of Protein Isoforms in Human Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Jinxiong Wei ◽  
Elena Zaika ◽  
Alexander Zaika
Keyword(s):  
Human Cancer ◽  
Critical Role ◽  
Protein Isoforms ◽  
Biological Processes ◽  
Family Role ◽  
P53 Family ◽  
Curative Therapy ◽  
Isoform Diversity ◽  
Alternative Mrna Splicing

TP53,TP63, andTP73genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.

scholarly journals Organization and chromosomal localization of the human ECEL1 (XCE) gene encoding a zinc metallopeptidase involved in the nervous control of respiration

2000 ◽  
Vol 346 (3) ◽  
pp. 611-616 ◽  
Author(s):  
Olivier VALDENAIRE ◽  
Elisabeth ROHRBACHER ◽  
An LANGEVELD ◽  
Anja SCHWEIZER ◽  
Carel MEIJERS
Keyword(s):  
Critical Role ◽  
Phylogenetic Study ◽  
Control Of Respiration ◽  
Chromosome 2 ◽  
Converting Enzyme ◽  
Gene Encoding ◽  
Nervous Control ◽  
Zinc Metalloprotease ◽  
Endothelin Converting Enzyme

ECEL1 (endothelin-converting enzyme-like 1; previously known as XCE) is a putative zinc metalloprotease that was identified recently on the basis of its strong identity with endothelin-converting enzyme. Although the physiological function of ECEL1 is unknown, inactivation of the corresponding gene in mice points to a critical role of this protein in the nervous control of respiration. In the present study we have characterized the human ECEL1 gene. It was located to region q36-q37 of chromosome 2 and shown to be composed of 18 exons spanning approx. 8 kb. The structure of the ECEL1 gene displays some striking similarities with those of genes of related metallopeptidases, supporting the hypothesis that they are all derived from a common ancestor. A short phylogenetic study describing the relationship between the various members of this gene family is also presented.

scholarly journals m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

2020 ◽  
Author(s):  
Yuhuan Li ◽  
Qingyang Zhang ◽  
Guanshen Cui ◽  
Fang Zhao ◽  
Xin Tian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Liver Lipid ◽  
Critical Role ◽  
Biological Processes ◽  
High Fat ◽  
Rna Methylation ◽  
Key Factor

AbstractN6-methyladenosine (m6A) RNA methylation is one of the most abundant modifications on mRNAs and plays an important role in various biological processes. The formation of m6A is catalysed by a methyltransferase complex containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in liver lipid and glucose metabolism remain unclear. Here, we show that both Mettl3 expression and m6A level increased in the liver of mice with High Fat Diet (HFD)-induced metabolic disorders, and overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. Hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss causes extended RNA half-lives of metabolism-related genes, consequently protects mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.

MicroRNA regulation of BAG3

2022 ◽  
pp. 153537022110669
Author(s):  
Madhu V Singh ◽  
Karthik Dhanabalan ◽  
Joseph Verry ◽  
Ayotunde O Dokun
Keyword(s):  
Critical Role ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Biological Processes ◽  
Adaptive Responses ◽  
Protein Coding ◽  
Microrna Regulation ◽  
A Cell ◽  
Artery Disease

B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that modulates major biological processes, including apoptosis, autophagy, and development to promote cellular adaptive responses to stress stimuli. Although BAG3 is constitutively expressed in several cell types, its expression is also inducible and is regulated by microRNAs (miRNAs). miRNAs are small non-coding RNAs that mostly bind to the 3′-UTR (untranslated region) of mRNAs to inhibit their translation or to promote their degradation. miRNAs can potentially regulate over 50% of the protein-coding genes in a cell and therefore are involved in the regulation of all major functions, including cell differentiation, growth, proliferation, apoptosis, and autophagy. Dysregulation of miRNA expression is associated with pathogenesis of numerous diseases, including peripheral artery disease (PAD). BAG3 plays a critical role in regulating the response of skeletal muscle cells to ischemia by its ability to regulate autophagy. However, the biological role of miRNAs in the regulation of BAG3 in biological processes has only been elucidated recently. In this review, we discuss how miRNA may play a key role in regulating BAG3 expression under normal and pathological conditions.

scholarly journals Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide

2016 ◽  
Vol 212 (5) ◽  
pp. 545-560 ◽  
Author(s):  
Chenran Wang ◽  
Song Chen ◽  
Syn Yeo ◽  
Gizem Karsli-Uzunbas ◽  
Eileen White ◽  
...  
Keyword(s):  
Stem Cells ◽  
Superoxide Dismutase ◽  
Neural Stem Cells ◽  
Knockout Mice ◽  
Critical Role ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Aggregate Formation ◽  
Conditional Knockout Mice

Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control.

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