Early diverging fungus Mucor circinelloides lacks centromeric histone CENP-A and displays a mosaic of point and regional centromeres

AbstractCentromeres are rapidly evolving across eukaryotes, despite performing a conserved function to ensure high fidelity chromosome segregation. CENP-A chromatin is a hallmark of a functional centromere in most organisms. Due to its critical role in kinetochore architecture, the loss of CENP-A is tolerated in only a few organisms, many of which possess holocentric chromosomes. Here, we characterize the consequence of the loss of CENP-A in the fungal kingdom. Mucor circinelloides, an opportunistic human pathogen, lacks CENP-A along with the evolutionarily conserved CENP-C, but assembles a monocentric chromosome with a localized kinetochore complex throughout the cell cycle. Mis12 and Dsn1, two conserved kinetochore proteins were found to bind nine short overlapping regions, each comprising an ∼200-bp AT-rich sequence followed by a centromere-specific conserved motif that echoes the structure of budding yeast point centromeres. Resembling fungal regional centromeres, these core centromere regions are embedded in large genomic expanses devoid of genes yet marked by Grem-LINE1s, a novel retrotransposable element silenced by the Dicer-dependent RNAi pathway. Our results suggest that these hybrid features of point and regional centromeres arose from the absence of CENP-A, thus defining novel mosaic centromeres in this early-diverging fungus.

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Implications of the Evolutionary Trajectory of Centromeres in the Fungal Kingdom

Annual Review of Microbiology ◽

10.1146/annurev-micro-011720-122512 ◽

2020 ◽

Vol 74 (1) ◽

pp. 835-853

Author(s):

Krishnendu Guin ◽

Lakshmi Sreekumar ◽

Kaustuv Sanyal

Keyword(s):

Chromosome Segregation ◽

Fungal Species ◽

Last Common Ancestor ◽

Yeast Saccharomyces Cerevisiae ◽

Evolutionary Trajectory ◽

Centromeric Chromatin ◽

Evolutionarily Conserved ◽

Sequence Elements ◽

Fundamental Biological Process ◽

Fungal Kingdom

Chromosome segregation during the cell cycle is an evolutionarily conserved, fundamental biological process. Dynamic interaction between spindle microtubules and the kinetochore complex that assembles on centromere DNA is required for faithful chromosome segregation. The first artificial minichromosome was constructed by cloning the centromere DNA of the budding yeast Saccharomyces cerevisiae. Since then, centromeres have been identified in >60 fungal species. The DNA sequence and organization of the sequence elements are highly diverse across these fungal centromeres. In this article, we provide a comprehensive view of the evolution of fungal centromeres. Studies of this process facilitated the identification of factors influencing centromere specification, maintenance, and propagation through many generations. Additionally, we discuss the unique features and plasticity of centromeric chromatin and the involvement of centromeres in karyotype evolution. Finally, we discuss the implications of recurrent loss of RNA interference (RNAi) and/or heterochromatin components on the trajectory of the evolution of fungal centromeres and propose the centromere structure of the last common ancestor of three major fungal phyla—Ascomycota, Basidiomycota, and Mucoromycota.

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Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses

Pathogens ◽

10.3390/pathogens10030286 ◽

2021 ◽

Vol 10 (3) ◽

pp. 286

Author(s):

Mary Frances Nakamya ◽

Moses B. Ayoola ◽

Leslie A. Shack ◽

Mirghani Mohamed ◽

Edwin Swiatlo ◽

...

Keyword(s):

Stress Responses ◽

Critical Role ◽

Acid Stress ◽

Arginine Decarboxylase ◽

Arginine Deiminase ◽

Dependent Manner ◽

Cellular Processes ◽

Opportunistic Human Pathogen ◽

Thiol Peroxidase ◽

The Impact

Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host–pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.

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Atypical Protein Kinase C Is Involved in the Evolutionarily Conserved Par Protein Complex and Plays a Critical Role in Establishing Epithelia-Specific Junctional Structures

The Journal of Cell Biology ◽

10.1083/jcb.152.6.1183 ◽

2001 ◽

Vol 152 (6) ◽

pp. 1183-1196 ◽

Cited By ~ 292

Author(s):

Atsushi Suzuki ◽

Tomoyuki Yamanaka ◽

Tomonori Hirose ◽

Naoyuki Manabe ◽

Keiko Mizuno ◽

...

Keyword(s):

Epithelial Cells ◽

Cell Polarity ◽

Protein Complex ◽

Mdck Cells ◽

Critical Role ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Surface Polarity ◽

C Elegans ◽

Evolutionarily Conserved

We have previously shown that during early Caenorhabditis elegans embryogenesis PKC-3, a C. elegans atypical PKC (aPKC), plays critical roles in the establishment of cell polarity required for subsequent asymmetric cleavage by interacting with PAR-3 [Tabuse, Y., Y. Izumi, F. Piano, K.J. Kemphues, J. Miwa, and S. Ohno. 1998. Development (Camb.). 125:3607–3614]. Together with the fact that aPKC and a mammalian PAR-3 homologue, aPKC-specific interacting protein (ASIP), colocalize at the tight junctions of polarized epithelial cells (Izumi, Y., H. Hirose, Y. Tamai, S.-I. Hirai, Y. Nagashima, T. Fujimoto, Y. Tabuse, K.J. Kemphues, and S. Ohno. 1998. J. Cell Biol. 143:95–106), this suggests a ubiquitous role for aPKC in establishing cell polarity in multicellular organisms. Here, we show that the overexpression of a dominant-negative mutant of aPKC (aPKCkn) in MDCK II cells causes mislocalization of ASIP/PAR-3. Immunocytochemical analyses, as well as measurements of paracellular diffusion of ions or nonionic solutes, demonstrate that the biogenesis of the tight junction structure itself is severely affected in aPKCkn-expressing cells. Furthermore, these cells show increased interdomain diffusion of fluorescent lipid and disruption of the polarized distribution of Na+,K+-ATPase, suggesting that epithelial cell surface polarity is severely impaired in these cells. On the other hand, we also found that aPKC associates not only with ASIP/PAR-3, but also with a mammalian homologue of C. elegans PAR-6 (mPAR-6), and thereby mediates the formation of an aPKC-ASIP/PAR-3–PAR-6 ternary complex that localizes to the apical junctional region of MDCK cells. These results indicate that aPKC is involved in the evolutionarily conserved PAR protein complex, and plays critical roles in the development of the junctional structures and apico-basal polarization of mammalian epithelial cells.

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MicroRNAs in Cardiac Autophagy: Small Molecules and Big Role

Cells ◽

10.3390/cells7080104 ◽

2018 ◽

Vol 7 (8) ◽

pp. 104 ◽

Cited By ~ 22

Author(s):

Teng Sun ◽

Meng-Yang Li ◽

Pei-Feng Li ◽

Ji-Min Cao

Keyword(s):

Cardiac Fibrosis ◽

Heart Diseases ◽

Critical Role ◽

Transcriptional Gene Silencing ◽

Close Link ◽

Post Transcriptional Gene Silencing ◽

Evolutionarily Conserved ◽

Cardiac Disorders ◽

Cellular Components

Autophagy, which is an evolutionarily conserved process according to the lysosomal degradation of cellular components, plays a critical role in maintaining cell homeostasis. Autophagy and mitochondria autophagy (mitophagy) contribute to the preservation of cardiac homeostasis in physiological settings. However, impaired or excessive autophagy is related to a variety of diseases. Recently, a close link between autophagy and cardiac disorders, including myocardial infarction, cardiac hypertrophy, cardiomyopathy, cardiac fibrosis, and heart failure, has been demonstrated. MicroRNAs (miRNAs) are a class of small non-coding RNAs with a length of approximately 21–22 nucleotides (nt), which are distributed widely in viruses, plants, protists, and animals. They function in mediating the post-transcriptional gene silencing. A growing number of studies have demonstrated that miRNAs regulate cardiac autophagy by suppressing the expression of autophagy-related genes in a targeted manner, which are involved in the pathogenesis of heart diseases. This review summarizes the role of microRNAs in cardiac autophagy and related cardiac disorders. Furthermore, we mainly focused on the autophagy regulation pathways, which consisted of miRNAs and their targeted genes.

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Cul4-Ddb1 ubiquitin ligases facilitate DNA replication-coupled sister chromatid cohesion through regulation of cohesin acetyltransferase Esco2

10.1101/414888 ◽

2018 ◽

Cited By ~ 1

Author(s):

Haitao Sun ◽

Jiaxin Zhang ◽

Jingjing Zhang ◽

Zhen Li ◽

Qinhong Cao ◽

...

Keyword(s):

Dna Replication ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

Critical Role ◽

E3 Ubiquitin Ligase ◽

Ubiquitin Ligases ◽

Sister Chromatid Cohesion ◽

Vital Role ◽

Chromatid Cohesion ◽

Evolutionarily Conserved

AbstractCohesin acetyltransferases Esco1 and Esco2 play a vital role in establishing sister chromatid cohesion. How Esco1 and Esco2 are controlled to achieve this in a DNA replication-coupled manner remains unclear in higher eukaryotes. Here we show that Cul4-RING ligases (CRL4s) play a critical role in sister chromatid cohesion in human cells. Depletion of Cul4A, Cul4B or Ddb1 subunits substantially reduces normal cohesion efficiency. We also show that Mms22L, a vertebrate ortholog of yeast Mms22, is one of Ddb1 and Cul4-associated factors (DCAFs) involved in cohesion. Several lines of evidence suggest a selective interaction of CRL4s with Esco2, but not Esco1. Depletion of either CRL4s or Esco2 causes a defect in Smc3 acetylation which can be rescued by HDAC8 inhibition. More importantly, both CRL4s and PCNA act as mediators for efficiently stabilizing Esco2 on chromatin and catalyzing Smc3 acetylation. Taken together, we propose an evolutionarily conserved mechanism in which CRL4s and PCNA regulate Esco2-dependent establishment of sister chromatid cohesion.Author summaryWe identified human Mms22L as a substrate specific adaptor of Cul4-Ddb1 E3 ubiquitin ligase. Downregulation of Cul4A, Cul4B or Ddb1 subunit causes reduction of acetylated Smc3, via interaction with Esco2 acetyltransferase, and then impairs sister chromatid cohesion in 293T cells. We found functional complementation between Cul4-Ddb1-Mms22L E3 ligase and Esco2 in Smc3 acetylation and sister chromatid cohesion. Interestingly, both Cul4-Ddb1 E3 ubiquitin ligase and PCNA contribute to Esco2 mediated Smc3 acetylation. To summarise, we demonstrated an evolutionarily conserved mechanism in which Cul4-Ddb1 E3 ubiquitin ligases and PCNA regulate Esco2-dependent establishment of sister chromatid cohesion.

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Viral strategies of manipulating autophagy to benefit infection

10.20944/preprints201905.0126.v1 ◽

2019 ◽

Author(s):

Ho Him Wong ◽

Sumana Sanyal

Keyword(s):

Rna Virus ◽

Critical Role ◽

Intracellular Pathogens ◽

Virus Infections ◽

Central Process ◽

Conservation Of Energy ◽

Evolutionarily Conserved ◽

Cellular Defence ◽

Host Metabolism ◽

Fine Tune

Autophagy is an evolutionarily conserved central process in host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention.

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Abstract 2987: A critical role of translocated promoter region (Tpr) in chromosome segregation and cell division in cancer

10.1158/1538-7445.am2011-2987 ◽

2011 ◽

Author(s):

Tatsuyoshi Funasaka ◽

Hiroshi Nakano ◽

Richard Wong

Keyword(s):

Cell Division ◽

Chromosome Segregation ◽

Promoter Region ◽

Critical Role

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Autophagy Defects in Skeletal Myopathies

Annual Review of Pathology Mechanisms of Disease ◽

10.1146/annurev-pathmechdis-012419-032618 ◽

2020 ◽

Vol 15 (1) ◽

pp. 261-285 ◽

Cited By ~ 6

Author(s):

Marta Margeta

Keyword(s):

Clinical Presentation ◽

Critical Role ◽

Lysosomal Degradation ◽

Cellular Mechanisms ◽

Biological Stress ◽

Evolutionarily Conserved ◽

Different Types ◽

Muscle Homeostasis ◽

Catabolic Process ◽

Cellular Organelles

Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies; the observed autophagy defects differ from disease to disease but have been shown to involve all steps of the autophagic cascade (from induction to lysosomal cargo degradation) and to impair both bulk and selective autophagy. To highlight the molecular and cellular mechanisms that are shared among different myopathies with deficient autophagy, these disorders are discussed based on the nature of the underlying autophagic defect rather than etiology or clinical presentation.

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Mechanism of APC/CCDC20 activation by mitotic phosphorylation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1604929113 ◽

2016 ◽

Vol 113 (19) ◽

pp. E2570-E2578 ◽

Cited By ~ 69

Author(s):

Renping Qiao ◽

Florian Weissmann ◽

Masaya Yamaguchi ◽

Nicholas G. Brown ◽

Ryan VanderLinden ◽

...

Keyword(s):

Chromosome Segregation ◽

Mitotic Checkpoint ◽

Anaphase Promoting Complex ◽

Loop Region ◽

Evolutionarily Conserved ◽

Terminal Loop ◽

Different Types ◽

Mitotic Phosphorylation ◽

Mitotic Checkpoint Complex

Chromosome segregation and mitotic exit are initiated by the 1.2-MDa ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) and its coactivator CDC20 (cell division cycle 20). To avoid chromosome missegregation, APC/CCDC20 activation is tightly controlled. CDC20 only associates with APC/C in mitosis when APC/C has become phosphorylated and is further inhibited by a mitotic checkpoint complex until all chromosomes are bioriented on the spindle. APC/C contains 14 different types of subunits, most of which are phosphorylated in mitosis on multiple sites. However, it is unknown which of these phospho-sites enable APC/CCDC20 activation and by which mechanism. Here we have identified 68 evolutionarily conserved mitotic phospho-sites on human APC/C bound to CDC20 and have used the biGBac technique to generate 47 APC/C mutants in which either all 68 sites or subsets of them were replaced by nonphosphorylatable or phospho-mimicking residues. The characterization of these complexes in substrate ubiquitination and degradation assays indicates that phosphorylation of an N-terminal loop region in APC1 is sufficient for binding and activation of APC/C by CDC20. Deletion of the N-terminal APC1 loop enables APC/CCDC20 activation in the absence of mitotic phosphorylation or phospho-mimicking mutations. These results indicate that binding of CDC20 to APC/C is normally prevented by an autoinhibitory loop in APC1 and that its mitotic phosphorylation relieves this inhibition. The predicted location of the N-terminal APC1 loop implies that this loop controls interactions between the N-terminal domain of CDC20 and APC1 and APC8. These results reveal how APC/C phosphorylation enables CDC20 to bind and activate the APC/C in mitosis.

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