scholarly journals Centromeres under Pressure: Evolutionary Innovation in Conflict with Conserved Function

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 912 ◽  
Author(s):  
Elisa Balzano ◽  
Simona Giunta
Keyword(s):  
Genome Instability ◽  
Dynamic Features ◽  
Sequence Composition ◽  
Evolutionary Innovation ◽  
Microtubule Attachment ◽  
Meiotic Transmission ◽  
Secondary Dna Structures ◽  
Dna 2 ◽  
And Function ◽  
Mitosis And Meiosis

Centromeres are essential genetic elements that enable spindle microtubule attachment for chromosome segregation during mitosis and meiosis. While this function is preserved across species, centromeres display an array of dynamic features, including: (1) rapidly evolving DNA; (2) wide evolutionary diversity in size, shape and organization; (3) evidence of mutational processes to generate homogenized repetitive arrays that characterize centromeres in several species; (4) tolerance to changes in position, as in the case of neocentromeres; and (5) intrinsic fragility derived by sequence composition and secondary DNA structures. Centromere drive underlies rapid centromere DNA evolution due to the “selfish” pursuit to bias meiotic transmission and promote the propagation of stronger centromeres. Yet, the origins of other dynamic features of centromeres remain unclear. Here, we review our current understanding of centromere evolution and plasticity. We also detail the mutagenic processes proposed to shape the divergent genetic nature of centromeres. Changes to centromeres are not simply evolutionary relics, but ongoing shifts that on one side promote centromere flexibility, but on the other can undermine centromere integrity and function with potential pathological implications such as genome instability.

Epigenetic specification of centromeresThis paper is one of a selection of papers published in this Special Issue, entitled 29th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 273-282 ◽  
Author(s):  
Yamini Dalal
Keyword(s):  
Peer Review Process ◽  
Pericentric Heterochromatin ◽  
Microtubule Attachment ◽  
New Findings ◽  
Histone H3 Variant ◽  
Associated Proteins ◽  
Chromatin Folding ◽  
Nucleosomal Structure ◽  
And Function ◽  
Mitosis And Meiosis

Centromeres are the discrete sites of spindle microtubule attachment on chromosomes during mitosis and meiosis in all eukaryotes. These highly specialized chromatin structures typically occupy the same site for thousands of generations, yet the mechanism by which centromeres are established, maintained, and function remain a mystery. In metazoans, centromeric DNA sequence has proven not to be the key determinant of centromeric identity; therefore, centromeres are thought to be epigenetically specified by their specialized chromatin structure. In all eukaryotes, the centromere-specific histone H3 variant CenH3 replaces canonical H3 within nucleosomes at centric chromatin. This specialized nucleosome is the building block upon which all other centromere-associated proteins depend. This review highlights exciting new findings that have resulted in a paradigm shift in our understanding of CenH3 assembly into centromeric chromatin, CenH3 nucleosomal structure, CenH3 chromatin folding, the contribution of these factors to centromeric identity, and finally, the intimate role cell-cycle-regulated transcription and pericentric heterochromatin play in the maintenance and integrity of centromeres.

scholarly journals Centromere Protein B Null Mice are Mitotically and Meiotically Normal but Have Lower Body and Testis Weights

1998 ◽  
Vol 141 (2) ◽  
pp. 309-319 ◽  
Author(s):  
Damien F. Hudson ◽  
Kerry J. Fowler ◽  
Elizabeth Earle ◽  
Richard Saffery ◽  
Paul Kalitsis ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Conflicting Evidence ◽  
Body Weights ◽  
Reduced Rate ◽  
And Function ◽  
Centromere Assembly ◽  
Mitosis And Meiosis

CENP-B is a constitutive centromere DNA-binding protein that is conserved in a number of mammalian species and in yeast. Despite this conservation, earlier cytological and indirect experimental studies have provided conflicting evidence concerning the role of this protein in mitosis. The requirement of this protein in meiosis has also not previously been described. To resolve these uncertainties, we used targeted disruption of the Cenpb gene in mouse to study the functional significance of this protein in mitosis and meiosis. Male and female Cenpb null mice have normal body weights at birth and at weaning, but these subsequently lag behind those of the heterozygous and wild-type animals. The weight and sperm content of the testes of Cenpb null mice are also significantly decreased. Otherwise, the animals appear developmentally and reproductively normal. Cytogenetic fluorescence-activated cell sorting and histological analyses of somatic and germline tissues revealed no abnormality. These results indicate that Cenpb is not essential for mitosis or meiosis, although the observed weight reduction raises the possibility that Cenpb deficiency may subtly affect some aspects of centromere assembly and function, and result in reduced rate of cell cycle progression, efficiency of microtubule capture, and/or chromosome movement. A model for a functional redundancy of this protein is presented.

Environmental–biomechanical reciprocity and the evolution of plant material properties

2021 ◽  
Author(s):  
Karl J Niklas ◽  
Frank W Telewski
Keyword(s):  
Physical Environment ◽  
Structural Changes ◽  
Abiotic Factors ◽  
Biotic Interactions ◽  
Cellular Solids ◽  
Form And Function ◽  
Evolutionary Innovation ◽  
Plant Form ◽  
And Function ◽  
Abiotic Environmental Factors

Abstract Abiotic–biotic interactions have shaped organic evolution since life first began. Abiotic factors influence growth, survival, and reproductive success, whereas biotic responses to abiotic factors have changed the physical environment (and indeed created new environments). This reciprocity is well illustrated by land plants who begin and end their existence in the same location while growing in size over the course of years or even millennia, during which environment factors change over many orders of magnitude. A biomechanical, ecological, and evolutionary perspective reveals that plants are (i) composed of materials (cells and tissues) that function as cellular solids (i.e. materials composed of one or more solid and fluid phases); (ii) that have evolved greater rigidity (as a consequence of chemical and structural changes in their solid phases); (iii) allowing for increases in body size and (iv) permitting acclimation to more physiologically and ecologically diverse and challenging habitats; which (v) have profoundly altered biotic as well as abiotic environmental factors (e.g. the creation of soils, carbon sequestration, and water cycles). A critical component of this evolutionary innovation is the extent to which mechanical perturbations have shaped plant form and function and how form and function have shaped ecological dynamics over the course of evolution.

scholarly journals Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1690
Author(s):  
Louise Pinet ◽  
Nadine Assrir ◽  
Carine van Heijenoort
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Domain ◽  
Cellular Motility ◽  
Dynamic Features ◽  
Sh2 Domains ◽  
Intrinsically Disordered ◽  
Src Homology ◽  
Regulation Functions ◽  
And Function

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.

scholarly journals Flow Chart Generation-Based Source Code Similarity Detection Using Process Mining

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Feng Zhang ◽  
Lulu Li ◽  
Cong Liu ◽  
Qingtian Zeng
Keyword(s):  
Computer Programming ◽  
Process Mining ◽  
Source Code ◽  
Plagiarism Detection ◽  
Dynamic Features ◽  
Code Obfuscation ◽  
Loop Unrolling ◽  
Similarity Detection ◽  
Flow Charts ◽  
And Function

Source code similarity detection has extensive applications in computer programming teaching and software intellectual property protection. In the teaching of computer programming courses, students may utilize some complex source code obfuscation techniques, e.g., opaque predicates, loop unrolling, and function inlining and outlining, to reduce the similarity between code fragments and avoid the plagiarism detection. Existing source code similarity detection approaches only consider static features of source code, making it difficult to cope with more complex code obfuscation techniques. In this paper, we propose a novel source code similarity detection approach by considering the dynamic features at runtime of source code using process mining. More specifically, given two pieces of source code, their running logs are obtained by source code instrumentation and execution. Next, process mining is used to obtain the flow charts of the two pieces of source code by analyzing their collected running logs. Finally, similarity of the two pieces of source code is measured by computing the similarity of these two flow charts. Experimental results show that the proposed approach can deal with more complex obfuscation techniques including opaque predicates and loop unrolling as well as function inlining and outlining, which cannot be handled by existing work properly. Therefore, we argue that our approach can defeat commonly used code obfuscation techniques more effectively for source code similarity detection than the existing state-of-the-art approaches.

scholarly journals The Maize Homologue of the Cell Cycle Checkpoint Protein MAD2 Reveals Kinetochore Substructure and Contrasting Mitotic and Meiotic Localization Patterns

1999 ◽  
Vol 145 (3) ◽  
pp. 425-435 ◽  
Author(s):  
Hong-Guo Yu ◽  
Michael G. Muszynski ◽  
R. Kelly Dawe
Keyword(s):  
Cell Cycle ◽  
Spindle Assembly ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Microtubule Attachment ◽  
Checkpoint Pathway ◽  
Outer Domain ◽  
Cycle Checkpoint ◽  
Mitosis And Meiosis ◽  
Meiosis I

We have identified a maize homologue of yeast MAD2, an essential component in the spindle checkpoint pathway that ensures metaphase is complete before anaphase begins. Combined immunolocalization of MAD2 and a recently cloned maize CENPC homologue indicates that MAD2 localizes to an outer domain of the prometaphase kinetochore. MAD2 staining was primarily observed on mitotic kinetochores that lacked attached microtubules; i.e., at prometaphase or when the microtubules were depolymerized with oryzalin. In contrast, the loss of MAD2 staining in meiosis was not correlated with initial microtubule attachment but was correlated with a measure of tension: the distance between homologous or sister kinetochores (in meiosis I and II, respectively). Further, the tension-sensitive 3F3/2 phosphoepitope colocalized, and was lost concomitantly, with MAD2 staining at the meiotic kinetochore. The mechanism of spindle assembly (discussed here with respect to maize mitosis and meiosis) is likely to affect the relative contributions of attachment and tension. We support the idea that MAD2 is attachment-sensitive and that tension stabilizes microtubule attachments.

scholarly journals Phosphatase-Regulated Recruitment of the Spindle and Kinetochore Associated (SKA) Complex to Kinetochores

2017 ◽  
Author(s):  
Sushama Sivakumar ◽  
Gary J. Gorbsky
Keyword(s):  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Spindle Checkpoint ◽  
Checkpoint Signaling ◽  
Mitotic Kinases ◽  
Feedback Cycle ◽  
Microtubule Attachment ◽  
Phosphatase 2A ◽  
Summary Statement ◽  
And Function

ABSTRACTKinetochores move chromosomes on dynamic spindle microtubules and regulate cell cycle progression by signaling the spindle checkpoint. The Spindle and Kinetochore-Associated (Ska) Complex, a hexamer composed of two copies of Ska1, Ska2 and Ska3, participates in both roles. The mitotic kinases, Cdk1, Aurora B, Plk1, Mps1 and Bub1 play key, overlapping tasks in regulating chromosome movement and checkpoint signaling. However, roles for the phosphatases that oppose these kinases are more poorly defined. Recently, we showed that Ska1 is important for recruiting protein phosphatase 1 (PP1) to kinetochores. Here we show that PP1 and protein phosphatase 2A (PP2A) both promote accumulation of Ska at kinetochores. Depletion of PP1 or PP2A by siRNA reduces Ska binding at kinetochores, impairs alignment of chromosomes to the spindle midplane, and causes metaphase delay or arrest, phenotypes also seen after depletion of Ska. Tethering of PP1 to the kinetochore protein Nuf2 promotes Ska recruitment to kinetochores, and reduces mitotic defects seen after Ska depletion. We propose that kinetochore-associated phosphatases generate a positive feedback cycle to reinforce Ska complex accumulation and function at kinetochores.SUMMARY STATEMENTPhosphatases reinforce recruitment of the Ska complex at kinetochores to stabilize microtubule attachment and oppose spindle checkpoint signaling.

scholarly journals A high throughput bispecific antibody discovery pipeline

2021 ◽  
Author(s):  
Aude I. Segaliny ◽  
Jayapriya Jayaraman ◽  
Xiaoming Chen ◽  
Jonathan Chong ◽  
Ryan Luxon ◽  
...  
Keyword(s):  
Single Cell ◽  
High Throughput ◽  
High Throughput Screening ◽  
In Vitro Cytotoxicity ◽  
Functional Screening ◽  
Sequence Composition ◽  
Single Cell Pcr ◽  
Screening Efficiency ◽  
And Function

AbstractBispecific antibodies (BsAbs) represent an emerging class of immunotherapy but inefficiency in the current BsAb discovery paradigm has limited their broad clinical availability. Here we report a high throughput, agnostic, single-cell-based BsAb functional screening pipeline, comprising molecular and cell engineering for efficient generation of BsAb library cells, followed by functional interrogation at the single-cell level to identify and sort positive clones and downstream sequence identification with single-cell PCR and sequencing and functionality characterization. Using a CD19xCD3 bispecific T cell engager (BiTE) as a model system, we demonstrate that our single cell platform possesses a high throughput screening efficiency of up to one and half million variant library cells per run and can isolate rare functional clones at low abundance of 0.008%. Using a complex CD19xCD3 BiTE-expressing cell library with approximately 22,300 unique variants comprising combinatorially varied scFvs, connecting linkers and VL/VH orientations, we have identified 98 unique clones including extremely rare ones (∼ 0.001% abundance). We also discovered BiTEs that exhibit novel properties contradictory to conventional wisdom, including harboring rigid scFv connecting peptide linkers yet with in vitro cytotoxicity comparable to that of clinically approved Blinatumomab. Through sequencing analyses on sorted BiTE clones, we discovered multiple design variable preferences for functionality including the CD19VL-VH– CD3VH-VL and CD19VH-VL–CD3VH-VL arrangements being the most favored orientation. Sequence analysis further interrogated the sequence composition of the CDRH3 domain in scFvs and identified amino acid residues conserved for function. We expect our single cell platform to not only significantly increase the development speed of high quality of new BsAb therapeutics for cancer and other disorders, but also enable identifying generalizable design principles for new BsAbs and other immunotherapeutics based on an in-depth understanding of the inter-relationships between sequence, structure, and function.

scholarly journals FANCD2 tunes the UPR preventing mitochondrial stress-­induced common fragile site instability

2019 ◽  
Author(s):  
Philippe Fernandes ◽  
Benoit Miotto ◽  
Claude Saint-Ruf ◽  
Viola Nähse ◽  
Silvia Ravera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Instability ◽  
Fragile Site ◽  
Transcriptional Response ◽  
Genomic Analysis ◽  
Fragile Sites ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Large Genes ◽  
Genomic Regions

AbstractCommon fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability relies on transcription- and replication-dependent mechanisms. Here, we uncover a role for the UBL5-dependent branch of the unfolded protein response pathway (UPR) in the maintenance of CFS stability. We show that genetic or pharmacological UPR activation induces CFS gene expression and concomitant relocalization of FANCD2, a master regulator of CFS stability, to CFSs. Furthermore, a genomic analysis of FANCD2 binding sites identified an enrichment for mitochondrial UPR transcriptional response elements in FANCD2 bound regions. We demonstrated that depletion of FANCD2 increases CFS gene transcription and their instability while also inducing mitochondrial dysfunction and triggering the activation of the UPR pathway. Depletion of UBL5, a mediator of the UPR, but not ATF4, reduces CFS gene expression and breakage in FANCD2-depleted cells. We thus demonstrate that FANCD2 recruitment and function at CFSs depends on transcription and UPR signaling, and in absence of transcription or UBL5, FANCD2 is dispensable for CFS stability. We propose that FANCD2 coordinates nuclear and mitochondrial activities by tuning the UPR to prevent genome instability.

Phosphorylation of histone H3 by Haspin regulates chromosome alignment and segregation during mitosis in maize

2020 ◽  
Author(s):  
Yang Liu ◽  
Chunhui Wang ◽  
Handong Su ◽  
James A Birchler ◽  
Fangpu Han
Keyword(s):  
Chromosome Segregation ◽  
Histone H3 ◽  
Heterochromatin Protein 1 ◽  
Heterochromatin Protein ◽  
Factor B ◽  
Microtubule Attachment ◽  
Chromosome Alignment ◽  
Chromosomal Passenger ◽  
Mitosis And Meiosis

Abstract In human cells, Haspin-mediated histone H3 threonine 3 (H3T3) phosphorylation promotes centromeric localization of the chromosomal passenger complex, thereby ensuring proper kinetochore–microtubule attachment. Haspin also binds to PDS5 cohesin-associated factor B (Pds5B), antagonizing the Wings apart-like protein homolog (Wapl)–Pds5B interaction and thus preventing Wapl from releasing centromeric cohesion during mitosis. However, the role of Haspin in plant chromosome segregation is not well understood. Here, we show that in maize (Zea mays) mitotic cells, ZmHaspin localized to the centromere during metaphase and anaphase, whereas it localized to the telomeres during meiosis. These results suggest that ZmHaspin plays different roles during mitosis and meiosis. Knockout of ZmHaspin led to decreased H3T3 phosphorylation and histone H3 serine 10 phosphorylation, and defects in chromosome alignment and segregation in mitosis. These lines of evidence suggest that Haspin regulates chromosome segregation in plants via the mechanism described for humans, namely, H3T3 phosphorylation. Plant Haspin proteins lack the RTYGA and PxVxL motifs needed to bind Pds5B and heterochromatin protein 1, and no obvious cohesion defects were detected in ZmHaspin knockout plants. Taken together, these results highlight the conserved but slightly different roles of Haspin proteins in cell division in plants and in animals.

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