scholarly journals Cornelia de Lange Syndrome-associated mutations in Smc1 cause both sister chromatid cohesion and cohesion-independent defects

2018 ◽  
Author(s):  
Jingrong Chen ◽  
Frank Wu ◽  
Dean Dawson ◽  
Susannah Rankin
Keyword(s):  
Chromosome Segregation ◽  
Developmental Disorders ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Critical Role ◽  
Cornelia De Lange Syndrome ◽  
Chromosome Loss ◽  
Genes Encoding ◽  
Cornelia De Lange ◽  
The Impact

AbstractCornelia de Lange Syndrome is a pervasive developmental disorder characterized by limb truncations, craniofacial abnormalities, and cognitive delays. This syndrome is a member of a class of developmental disorders referred to as cohesinopathies, which result from mutations in the genes encoding subunits or regulators of the cohesin complex. The phenotypic consequences of these mutations may reflect the critical role that cohesin plays in chromosome structure, its ability to tether sister chromatids together during cell cycle progression, or some combination of both. Here we show that a sensitized assay for chromosome loss in budding yeast can be used to assess the impact of Cornelia de Lange syndrome (CdLS)-associated mutations in the core cohesin subunit Smc1 on cohesin function. We find that the CdLS-associated mutations can be grouped into two classes based on their impact on chromosome segregation. One class of mutations includes those that are defective in promoting accurate chromosome segregation, some no better than the null allele. Another class promotes both accurate chromosome cohesion and segregation. Strikingly, the mutations that have no impact chromosome dynamics in this assay are clustered near each other in the context of the folded SMC1 protein suggesting a previously uncharacterized region of functional importance in higher eukaryotes. This analysis illustrates how budding yeast can be used to elucidate mechanisms important in human health and development.

scholarly journals The Role of Cdh1p in Maintaining Genomic Stability in Budding Yeast

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 489-503 ◽  
Author(s):  
Karen E Ross ◽  
Orna Cohen-Fix
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Chromosome Loss ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Growth Defects ◽  
Genes Encoding ◽  
Specificity Factor

Abstract Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G1 transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1Δ and mad2Δ single mutants, the mad2Δ cdh1Δ double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneous deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinetochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2Δ cdh1Δ and pds1Δ cdh1Δ strains were rescued by overexpressing Swe1p, a G2/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1Δ mutant strains with abnormal Cdc28p/Clb activity that interferes with proper chromosome segregation.

scholarly journals Reduced Mad2 expression keeps relaxed kinetochores from arresting budding yeast in mitosis

2011 ◽  
Vol 22 (14) ◽  
pp. 2448-2457 ◽  
Author(s):  
Erin L. Barnhart ◽  
Russell K. Dorer ◽  
Andrew W. Murray ◽  
Scott C. Schuyler
Keyword(s):  
Chromosome Segregation ◽  
Budding Yeast ◽  
Spindle Checkpoint ◽  
Chromosome Loss ◽  
Wild Type ◽  
Yeast Saccharomyces Cerevisiae ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Diploid Cells ◽  
Antimicrotubule Drugs

Chromosome segregation depends on the spindle checkpoint, which delays anaphase until all chromosomes have bound microtubules and have been placed under tension. The Mad1–Mad2 complex is an essential component of the checkpoint. We studied the consequences of removing one copy of MAD2 in diploid cells of the budding yeast, Saccharomyces cerevisiae. Compared to MAD2/MAD2 cells, MAD2/mad2Δ heterozygotes show increased chromosome loss and have different responses to two insults that activate the spindle checkpoint: MAD2/mad2Δ cells respond normally to antimicrotubule drugs but cannot respond to chromosomes that lack tension between sister chromatids. In MAD2/mad2Δ cells with normal sister chromatid cohesion, removing one copy of MAD1 restores the checkpoint and returns chromosome loss to wild-type levels. We conclude that cells need the normal Mad2:Mad1 ratio to respond to chromosomes that are not under tension.

scholarly journals A critical role for Apc in hematopoietic stem and progenitor cell survival

2008 ◽  
Vol 205 (9) ◽  
pp. 2163-2175 ◽  
Author(s):  
Zhijian Qian ◽  
Lina Chen ◽  
Anthony A. Fernald ◽  
Bart O. Williams ◽  
Michelle M. Le Beau
Keyword(s):  
Chromosome Segregation ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Cellular Functions ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Cell Cycle Entry ◽  
Genes Encoding

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.

scholarly journals The Impact of Bioactive Surfaces in the Early Stages of Osseointegration: An In Vitro Comparative Study Evaluating the HAnano® and SLActive® Super Hydrophilic Surfaces

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Rodrigo A. da Silva ◽  
Geórgia da Silva Feltran ◽  
Marcel Rodrigues Ferreira ◽  
Patrícia Fretes Wood ◽  
Fabio Bezerra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Cell Cycle Progression ◽  
Cellular Adhesion ◽  
Biological Behavior ◽  
Early Stages ◽  
Genes Encoding ◽  
Bioactive Surfaces ◽  
The Impact

There is an increased effort on developing novel and active surfaces in order to accelerate their osteointegration, such as nanosized crystalline hydroxyapatite coating (HAnano®). To better understand the biological behavior of osteoblasts grown on HAnano® surface, the set of data was compared with SLActive®, a hydrophilic sandblasted titanium surface. Methodologically, osteoblasts were seeded on both surfaces up to 72 hours, to allow evaluating cell adhesion, viability, and set of genes encoding proteins related with adhesion, proliferation, and differentiation. Our data shows HAnano® displays an interesting substrate to support cell adhesion with typical spread morphologic cells, while SLActive®-adhering cells presented fusiform morphology. Our data shows that the cellular adhesion mechanism was accompanied with upexpression of integrin β1, Fak, and Src, favoring the assembling of focal adhesion platforms and coupling cell cycle progression (upmodulating of Cdk2, Cdk4, and Cdk6 genes) in response to HAnano®. Additionally, both bioactive surfaces promoted osteoblast differentiation stimulus, by activating Runx2, Osterix, and Alp genes. Although both surfaces promoted Rankl gene expression, Opg gene expression was higher in SLActive® and this difference reflected on the Rankl/Opg ratio. Finally, Caspase1 gene was significantly upmodulated in response to HAnano® and it suggests an involvement of the inflammasome complex. Collectively, this study provides enough evidences to support that the nanohydroxyapatite-coated surface provides the necessary microenvironment to drive osteoblast performance on dental implants and these stages of osteogenesis are expected during the early stages of osseointegration.

5.14 THE IMPACT OF SELF-INJURIOUS BEHAVIORS OF CHILDREN WITH CORNELIA DE LANGE SYNDROME ON PARENTAL STRESS

2016 ◽  
Vol 55 (10) ◽  
pp. S188
Author(s):  
Chang Kim ◽  
Siddharth Srivastava ◽  
Priyadurga Kodi ◽  
Allyson LaRosa ◽  
Marco A. Grados
Keyword(s):  
Parental Stress ◽  
Cornelia De Lange Syndrome ◽  
Cornelia De Lange ◽  
The Impact

scholarly journals Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1075
Author(s):  
Angelo Selicorni ◽  
Milena Mariani ◽  
Antonella Lettieri ◽  
Valentina Massa
Keyword(s):  
Molecular Basis ◽  
Genetic Disorders ◽  
Basic Research ◽  
Cornelia De Lange Syndrome ◽  
Clinical Genetic ◽  
Number Of Patients ◽  
Genes Encoding ◽  
History Of ◽  
Minor Anomalies ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a genetic disease that exemplifies the evolution of knowledge in the field of rare genetic disorders. Originally described as a unique pattern of major and minor anomalies, over time this syndrome has been shown to be characterized by a significant variability of clinical expression. By increasing the number of patients described, knowledge of the natural history of the condition has been enriched with the demonstration of the relative frequency of various potential comorbidities. Since 2006, the discovery of CdLS’s molecular basis has shown an equally vast genetic heterogeneity linked to the presence of variants in genes encoding for the cohesin complex pathway. The most recent clinical-genetic data led to the classification of the “original syndrome” into a “clinical spectrum” that foresees the presence of classic patients, of non-classic forms, and of conditions that show a modest phenotypic overlapping with the original disease. Finally, the knowledge of the molecular basis of the disease has allowed the development of basic research projects that could lay the foundations for the development of possible innovative pharmacological treatments.

scholarly journals BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Pablo García-Gutiérrez ◽  
Mario García-Domínguez
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Complex Function ◽  
Clinical Manifestations ◽  
Cornelia De Lange Syndrome ◽  
Cohesin Complex ◽  
Developmental Defects ◽  
Cornelia De Lange

Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered a cohesinopathy together with other phenotypically related diseases because of their association with mutations in subunits of the cohesin complex. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably and, although their precise molecular mechanisms are not well defined yet, the potential pathomechanisms underlying these diverse developmental defects have been theoretically linked to alterations of the cohesin complex function. The cohesin complex plays a critical role in sister chromatid cohesion, but this function is not affected in CdLS. In the last decades, a non-cohesion-related function of this complex on transcriptional regulation has been well established and CdLS pathoetiology has been recently associated to gene expression deregulation. Up to 70% of CdLS cases are linked to mutations in the cohesin-loading factor NIPBL, which has been shown to play a prominent function on chromatin architecture and transcriptional regulation. Therefore, it has been suggested that CdLS can be considered a transcriptomopathy. Actually, CdLS-like phenotypes have been associated to mutations in chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most of which have no known direct association with cohesin. In the case of BRD4, a critical highly investigated transcriptional coregulator, an interaction with NIPBL has been recently revealed, providing evidence on their cooperation in transcriptional regulation of developmentally important genes. This new finding reinforces the notion of an altered gene expression program during development as the major etiological basis for CdLS. In this review, we intend to integrate the recent available evidence on the molecular mechanisms underlying the clinical manifestations of CdLS, highlighting data that favors a transcription-centered framework, which support the idea that CdLS could be conceptualized as a transcriptomopathy.

scholarly journals Gcn5p Plays an Important Role in Centromere Kinetochore Function in Budding Yeast

2007 ◽  
Vol 28 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Stefano Vernarecci ◽  
Prisca Ornaghi ◽  
AnaCristina Bâgu ◽  
Enrico Cundari ◽  
Paola Ballario ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Critical Role ◽  
Chromosome Loss ◽  
Cycle Progression ◽  
Kinetochore Assembly ◽  
Spindle Elongation ◽  
And Function ◽  
Insight Into ◽  
Kinetochore Function

ABSTRACT We report that the histone acetyltransferase Gcn5p is involved in cell cycle progression, whereas its absence induces several mitotic defects, including inefficient nuclear division, chromosome loss, delayed G2 progression, and spindle elongation. The fidelity of chromosome segregation is finely regulated by the close interplay between the centromere and the kinetochore, a protein complex hierarchically assembled in the centromeric DNA region, while disruption of GCN5 in mutants of inner components results in sick phenotype. These synthetic interactions involving the ADA complex lay the genetic basis for the critical role of Gcn5p in kinetochore assembly and function. We found that Gcn5p is, in fact, physically linked to the centromere, where it affects the structure of the variant centromeric nucleosome. Our findings offer a key insight into a Gcn5p-dependent epigenetic regulation at centromere/kinetochore in mitosis.

scholarly journals Gambaran Perkembangan Komunikasi Anak Cornelia de Lange Syndrome (CdLS)

2019 ◽  
Vol 2 (1) ◽  
pp. 27
Author(s):  
Tri Retno Indah Susanti ◽  
Meira Erawati ◽  
Dwi Retno Nurniningsih
Keyword(s):  
Play Therapy ◽  
Developmental Disorders ◽  
Developmental Disorder ◽  
Language Use ◽  
Speech Therapy ◽  
Cornelia De Lange Syndrome ◽  
Communication Development ◽  
Cornelia De Lange ◽  
Minor Criteria

Cornelia de Lange Syndrome (CdLS) adalah gangguan perkembangan multisistem yang dikaitkan dengan gangguan kognitif, malformasi dan gangguan wajah internal yang khas. Gangguan perkembangan yang terjadi pada Cornelia de Lange Syndrome (CdLS) adalah keterampilan berbahasa dan berbicara. Tujuan dari penelitian ini adalah melihat peningkatan perkembangan komunikasi anak Sindrom Cornelia de Lange (CdLS) setelah diberi intervensi  play therapy dan terapi wicaradengan menggunakan media gambar dan warna. Metodologi penelitian ini menggunakan desain studi kasus. Alat yang digunakan untuk mengukur kemampuan bahasa menggunakan DENVER II. Berdasarkan hasil penelitian pada 9 November 2018, anak berusia 3 tahun, 9 bulan, 3 hari dengan diagnosis medis Sindrom Cornelia de Lange (CdLS) dengan keluhan anak belum bisa bicara. Hasil pemeriksaan fisik menunjukkan terdapat bentuk khas yaitu alis mata menyatu ditengah, bulu mata panjang, terdapat juga kriteria minor. Hasil pemeriksaan DENVER II dari bahasa, anak masih seperti anak usia 18 bulan.  Berdasarkan hasil evaluasi setelah 1 bulan tindakan keperawatan dan kolaborasi dengan terapis, telah terjadi peningkatan komunikasi anak.Kata kunci: Cornelia de Lang Syndrome, Peningkatan perkembangan, terapi wicara.Description of Communication Development in Children with Cornelia De Lange Syndrome (Cdls)AbstractCornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder that is associated with cognitive impairments, malformations and internal and typical facial disorders. Developmental disorders that occur in Cornelia de Lange Syndrome (CdLS) are language skills and speech. The purpose of this study was to see the speed of communication development of children of Cornelia de Lange Syndrome (CdLS), after being given an intervention. Improve conversation by using play therapy using image and color media. The methodology of this research uses case study design. The tool used to measure the ability language use the DENVER II. Based on the results of the study on November 9, 2018, children aged 3 years, 9 months, 3 days with a medical diagnosis of Cornelia de Lange Syndrome (CdLS) were obtained with a comparison of children unable to speak. From the results of physical examination, there are typical forms, namely spies in the middle, long eyelashes, also there are minor criteria. The results of DENVER II examination of various children's languages are still like 18 months old children. Based on the evaluation results after 1 month of nursing actions and collaboration with the therapist, there has been an increase in communication of children with Cornelia de Lange Syndrome (CdLS).Key words: Cornelia de Lang Syndrome, Increased development, Speech therapy

Sign in / Sign up

Export Citation Format

Share Document