scholarly journals Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 1153-1169 ◽  
Author(s):  
Riddhiman K. Garge ◽  
Jon M. Laurent ◽  
Aashiq H. Kachroo ◽  
Edward M. Marcotte
Keyword(s):  
Gene Families ◽  
Growth Defect ◽  
Gene Duplications ◽  
Yeast Gene ◽  
Macromolecular Transport ◽  
Cellular Processes ◽  
Growth Defects ◽  
Yeast Strains ◽  
Human Genes ◽  
Interaction Partners

Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes, including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼81% of human cytoskeletal genes across seven gene families for their ability to complement a growth defect induced by inactivation or deletion of the corresponding yeast ortholog. In five of seven families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but failing to fully complement the cytoskeletal roles of their yeast orthologs, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.

scholarly journals Systematic humanization of the yeast cytoskeleton discerns functionally replaceable from divergent human genes

2019 ◽  
Author(s):  
Riddhiman K. Garge ◽  
Jon M. Laurent ◽  
Aashiq H. Kachroo ◽  
Edward M. Marcotte
Keyword(s):  
Gene Families ◽  
Growth Defect ◽  
Gene Duplications ◽  
Yeast Gene ◽  
Macromolecular Transport ◽  
Cellular Processes ◽  
Growth Defects ◽  
Yeast Strains ◽  
Human Genes ◽  
Interaction Partners

AbstractMany gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼85% of human cytoskeletal genes across 7 gene families for their ability to complement a growth defect induced by deletion of the corresponding yeast ortholog. In 5 of 7 families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but apparently failing to interact with components of the yeast cytoskeleton, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.

scholarly journals Functional Roles of Bromodomain Proteins in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3606
Author(s):  
Samuel P. Boyson ◽  
Cong Gao ◽  
Kathleen Quinn ◽  
Joseph Boyd ◽  
Hana Paculova ◽  
...  
Keyword(s):  
Open Chromatin ◽  
Structural Domains ◽  
Pharmacological Agents ◽  
Functional Roles ◽  
Cellular Processes ◽  
Protein Interactome ◽  
Interaction Partners ◽  
Recent Developments ◽  
Bromodomain Proteins ◽  
Chromatin Configuration

Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

scholarly journals Yeasts as Complementary Model Systems for the Study of the Pathological Repercussions of Enhanced Synphilin-1 Glycation and Oxidation

2021 ◽  
Vol 22 (4) ◽  
pp. 1677
Author(s):  
David Seynnaeve ◽  
Daniel P. Mulvihill ◽  
Joris Winderickx ◽  
Vanessa Franssens
Keyword(s):  
Lewy Bodies ◽  
Inhibitory Effect ◽  
Model Systems ◽  
Wild Type ◽  
Glyoxalase System ◽  
Inclusion Formation ◽  
Growth Defects ◽  
Yeast Strains ◽  
Autophagic Degradation ◽  
Detrimental Impact

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human SNCAIP, which encodes the Synphilin-1 protein, was expressed in Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in S. cerevisiae increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type S. pombe cells and strains deleted for either glo1+ or glo2+. Contrary to S. cerevisiae, however, no growth defects were observed upon expression of SNCAIP. Altogether, our findings show the relevance of yeasts, especially S. cerevisiae, as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases.

scholarly journals treeWidget: a BioJS component to visualise phylogenetic trees

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 49 ◽  
Author(s):  
Fabian Schreiber
Keyword(s):  
Phylogenetic Trees ◽  
Protein Domains ◽  
Gene Families ◽  
Sequence Information ◽  
Gene Duplications ◽  
Link Type ◽  
History Of ◽  
Conservation Patterns ◽  
Evolution Of Gene Families ◽  
The Web

Summary: Phylogenetic trees are widely used to represent the evolution of gene families. As the history of gene families can be complex (including lots of gene duplications), its visualisation can become a difficult task. A good/accurate visualisation of phylogenetic trees - especially on the web - allows easier understanding and interpretation of trees to help to reveal the mechanisms that shape the evolution of a specific set of gene/species. Here, I present treeWidget, a modular BioJS component to visualise phylogenetic trees on the web. Through its modularity, treeWidget can be easily customized to allow the display of sequence information, e.g. protein domains and alignment conservation patterns.Availability: http://github.com/biojs/biojs; http://dx.doi.org/10.5281/zenodo.7707

scholarly journals A Screen for Gene Paralogies Delineating Evolutionary Branching Order of Early Metazoa

2019 ◽  
Vol 10 (2) ◽  
pp. 811-826 ◽  
Author(s):  
Albert Erives ◽  
Bernd Fritzsch
Keyword(s):  
Phylogenetic Analyses ◽  
Gene Families ◽  
Single Copy ◽  
Gene Duplications ◽  
Nervous Systems ◽  
Evolutionary Diversification ◽  
Transmembrane Channel ◽  
Sensory Epithelia ◽  
Protein X ◽  
Ancient Gene

The evolutionary diversification of animals is one of Earth’s greatest marvels, yet its earliest steps are shrouded in mystery. Animals, the monophyletic clade known as Metazoa, evolved wildly divergent multicellular life strategies featuring ciliated sensory epithelia. In many lineages epithelial sensoria became coupled to increasingly complex nervous systems. Currently, different phylogenetic analyses of single-copy genes support mutually-exclusive possibilities that either Porifera or Ctenophora is sister to all other animals. Resolving this dilemma would advance the ecological and evolutionary understanding of the first animals and the evolution of nervous systems. Here we describe a comparative phylogenetic approach based on gene duplications. We computationally identify and analyze gene families with early metazoan duplications using an approach that mitigates apparent gene loss resulting from the miscalling of paralogs. In the transmembrane channel-like (TMC) family of mechano-transducing channels, we find ancient duplications that define separate clades for Eumetazoa (Placozoa + Cnidaria + Bilateria) vs. Ctenophora, and one duplication that is shared only by Eumetazoa and Porifera. In the Max-like protein X (MLX and MLXIP) family of bHLH-ZIP regulators of metabolism, we find that all major lineages from Eumetazoa and Porifera (sponges) share a duplicated gene pair that is sister to the single-copy gene maintained in Ctenophora. These results suggest a new avenue for deducing deep phylogeny by choosing rather than avoiding ancient gene paralogies.

Arabidopsis mtHSC70-1 plays important roles in the establishment of COX-dependent respiration and redox homeostasis

2019 ◽  
Vol 70 (20) ◽  
pp. 5575-5590 ◽  
Author(s):  
Shan-Shan Wei ◽  
Wei-Tao Niu ◽  
Xiao-Ting Zhai ◽  
Wei-Qian Liang ◽  
Meng Xu ◽  
...  
Keyword(s):  
Alternative Oxidase ◽  
Redox Homeostasis ◽  
Superoxide Dismutase 1 ◽  
Respiratory Pathway ◽  
Cellular Processes ◽  
Growth Defects ◽  
Alternative Respiratory Pathway ◽  
Abnormal Mitochondria ◽  
Shock Proteins ◽  
Severe Growth

Abstract The 70 kDa heat shock proteins function as molecular chaperones and are involved in diverse cellular processes. However, the functions of the plant mitochondrial HSP70s (mtHSC70s) remain unclear. Severe growth defects were observed in the Arabidopsis thaliana mtHSC70-1 knockout lines, mthsc70-1a and mthsc70-1b. Conversely, the introduction of the mtHSC70-1 gene into the mthsc70-1a background fully reversed the phenotypes, indicating that mtHSC70-1 is essential for plant growth. The loss of mtHSC70-1 functions resulted in abnormal mitochondria and alterations to respiration because of an inhibition of the cytochrome c oxidase (COX) pathway and the activation of the alternative respiratory pathway. Defects in COX assembly were observed in the mtHSC70-1 knockout lines, leading to decreased COX activity. The mtHSC70-1 knockout plants have increased levels of reactive oxygen species (ROS). The introduction of the Mn-superoxide dismutase 1 (MSD1) or the catalase 1 (CAT1) gene into the mthsc70-1a plants decreased ROS levels, reduced the expression of alternative oxidase, and partially rescued growth. Taken together, our data suggest that mtHSC70-1 plays important roles in the establishment of COX-dependent respiration.

scholarly journals Functional analysis of yeast gene families involved in metabolism of vitamins B1and B6

Yeast ◽  
2002 ◽  
Vol 19 (14) ◽  
pp. 1261-1276 ◽  
Author(s):  
Susana Rodríguez-Navarro ◽  
Bertrand Llorente ◽  
María Teresa Rodríguez-Manzaneque ◽  
Anna Ramne ◽  
Genoveva Uber ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Gene Families ◽  
Yeast Gene

scholarly journals Ancient Genome Duplications Did Not Structure the Human Hox-Bearing Chromosomes

2001 ◽  
Vol 11 (5) ◽  
pp. 771-780 ◽  
Author(s):  
Austin L. Hughes ◽  
Jack da Silva ◽  
Robert Friedman
Keyword(s):  
Phylogenetic Analysis ◽  
Gene Duplication ◽  
Genome Duplication ◽  
Gene Families ◽  
Gene Duplications ◽  
Human Chromosomes ◽  
Time Period ◽  
Genome Duplications

The fact that there are four homeobox (Hox) clusters in most vertebrates but only one in invertebrates is often cited as evidence for the hypothesis that two rounds of genome duplication by polyploidization occurred early in vertebrate history. In addition, it has been observed in humans and other mammals that numerous gene families include paralogs on two or more of the fourHox-bearing chromosomes (the chromosomes bearing theHox clusters; i.e., human chromosomes 2, 7, 12, and 17), and the existence of these paralogs has been taken as evidence that these genes were duplicated along with the Hox clusters by polyploidization. We tested this hypothesis by phylogenetic analysis of 42 gene families including members on two or more of the humanHox-bearing chromosomes. In 32 of these families there was evidence against the hypothesis that gene duplication occurred simultaneously with duplication of the Hox clusters. Phylogenies of 14 families supported the occurrence of one or more gene duplications before the origin of vertebrates, and of 15 gene duplication times estimated for gene families evolving in a clock-like manner, only six were dated to the same time period early in vertebrate history during which the Hox clusters duplicated. Furthermore, of gene families duplicated around the same time as the Hoxclusters, the majority showed topologies inconsistent with their having duplicated simultaneously with the Hox clusters. The results thus indicate that ancient events of genome duplication, if they occurred at all, did not play an important role in structuring the mammalian Hox-bearing chromosomes.

scholarly journals Induction of protein aggregation and starvation response by tRNA modification defects

2020 ◽  
Vol 66 (6) ◽  
pp. 1053-1057
Author(s):  
Roland Klassen ◽  
Alexander Bruch ◽  
Raffael Schaffrath
Keyword(s):  
Cellular Response ◽  
Anticodon Loop ◽  
Protein Aggregate ◽  
Starvation Response ◽  
Codon Recognition ◽  
Growth Defects ◽  
Yeast Strains ◽  
Transcriptional Changes ◽  
Decoding Efficiency ◽  
Synthetic Growth

Abstract Posttranscriptional modifications of anticodon loops contribute to the decoding efficiency of tRNAs by supporting codon recognition and loop stability. Consistently, strong synthetic growth defects are observed in yeast strains simultaneously lacking distinct anticodon loop modifications. These phenotypes are accompanied by translational inefficiency of certain mRNAs and disturbed protein homeostasis resulting in accumulation of protein aggregates. Different combinations of anticodon loop modification defects were shown to affect distinct tRNAs but provoke common transcriptional changes that are reminiscent of the cellular response to nutrient starvation. Multiple mechanisms may be involved in mediating inadequate starvation response upon loss of critical tRNA modifications. Recent evidence suggests protein aggregate induction to represent one such trigger.

scholarly journals Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

2015 ◽  
Vol 35 (12) ◽  
pp. 2203-2214 ◽  
Author(s):  
Muhammad Sohail ◽  
Jiuyong Xie
Keyword(s):  
Cell Cycle ◽  
Splice Variant ◽  
Splice Variants ◽  
Exon Skipping ◽  
Regulatory Elements ◽  
Cellular Processes ◽  
Human Genes ◽  
Splicing Regulatory Elements ◽  
Evolutionary Emergence ◽  
Nuclear Ribonucleoprotein

Alternative splicing contributes greatly to the diversification of mammalian proteomes, but the molecular basis for the evolutionary emergence of splice variants remains poorly understood. We have recently found a novel class of splicing regulatory elements between the polypyrimidine tract (Py) and 3′ AG (REPA) at intron ends in many human genes, including the multifunctionalPRMT5(for protein arginine methyltransferase 5) gene. The PRMT5 element is comprised of two G tracts that arise in most mammals and accompany significant exon skipping in human transcripts. The G tracts inhibit splicing by recruiting heterogeneous nuclear ribonucleoprotein (hnRNP) H and F (H/F) to reduce U2AF65 binding to the Py, causing exon skipping. The resulting novel shorter variant PRMT5S exhibits a histone H4R3 methylation effect similar to that seen with the original longer PRMT5L isoform but exhibits a distinct localization and preferential control of critical genes for cell cycle arrest at interphase in comparison to PRMT5L. This report thus provides a molecular mechanism for the evolutionary emergence of a novel splice variant with an opposite function in a fundamental cell process. The presence of REPA elements in a large group of genes implies their wider impact on different cellular processes for increased protein diversity in humans.

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