scholarly journals Chromatin rewiring mediates programmed evolvability via aneuploidy

2018 ◽  
Author(s):  
Cedric A. Brimacombe ◽  
Jordan E. Burke ◽  
Jahan-Yar Parsa ◽  
Jessica N. Witchley ◽  
Laura S. Burrack ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Phosphorylation Site ◽  
Rapid Evolution ◽  
Histone H3 ◽  
Antifungal Drugs ◽  
High Fidelity ◽  
Histone H2a ◽  
Human Pathogen ◽  
Chromosome Missegregation ◽  
Mitosis And Meiosis

Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis1, and yet specific aneuploidies can be adaptive during environmental stress2,3. Here, we identify a chromatin-based system for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire resistance to antifungal drugs4,5 and for ploidy reduction after mating6. We discovered that the ancestor of C. albicans and two related pathogens evolved a variant of histone H2A that lacks the conserved phosphorylation site for Bub1 kinase7, a key regulator of chromosome segregation1. Expression of this variant controls the rates of aneuploidy and antibiotic resistance in this species. Moreover, CENP-A/Cse4, the histone H3 that specifies centromeres, is depleted from tetraploid mating products and virtually eliminated from cells exposed to aneuploidy-promoting cues. Thus, changes in chromatin regulation can confer the capacity for rapid evolution in eukaryotes.

scholarly journals Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

2019 ◽  
Vol 219 (2) ◽  
Author(s):  
Cai Liang ◽  
Zhenlei Zhang ◽  
Qinfu Chen ◽  
Haiyan Yan ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Essential Role ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Chromosome Missegregation ◽  
Proper Timing ◽  
Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

scholarly journals The Opposing Functions of Protein Kinases and Phosphatases in Chromosome Bipolar Attachment

2019 ◽  
Vol 20 (24) ◽  
pp. 6182 ◽  
Author(s):  
Delaney Sherwin ◽  
Yanchang Wang
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Model Organism ◽  
Eukaryotic Cells ◽  
Genome Integrity ◽  
Chromosome Missegregation ◽  
Spindle Poles ◽  
Mitosis And Meiosis

Accurate chromosome segregation during cell division is essential to maintain genome integrity in all eukaryotic cells, and chromosome missegregation leads to aneuploidy and therefore represents a hallmark of many cancers. Accurate segregation requires sister kinetochores to attach to microtubules emanating from opposite spindle poles, known as bipolar attachment or biorientation. Recent studies have uncovered several mechanisms critical to chromosome bipolar attachment. First, a mechanism exists to ensure that the conformation of sister centromeres is biased toward bipolar attachment. Second, the phosphorylation of some kinetochore proteins destabilizes kinetochore attachment to facilitate error correction, but a protein phosphatase reverses this phosphorylation. Moreover, the activity of the spindle assembly checkpoint is regulated by kinases and phosphatases at the kinetochore, and this checkpoint prevents anaphase entry in response to faulty kinetochore attachment. The fine-tuned kinase/phosphatase balance at kinetochores is crucial for faithful chromosome segregation during both mitosis and meiosis. Here, we discuss the function and regulation of protein phosphatases in the establishment of chromosome bipolar attachment with a focus on the model organism budding yeast.

scholarly journals Molecular Basis for CPC-Sgo1 Interaction: Implications for Centromere Localisation and Function of the CPC

2021 ◽  
Author(s):  
Maria Alba Abad ◽  
Tanmay Gupta ◽  
Michael A Hadders ◽  
Amanda Meppelink ◽  
J Pepijn Wopken ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Molecular Basis ◽  
Hot Spot ◽  
Histone H3 ◽  
Direct Interaction ◽  
Histone H2a ◽  
Chromosomal Passenger ◽  
And Function ◽  
Affinity Interaction

AbstractThe Chromosomal Passenger Complex (CPC; consisting of Borealin, Survivin, INCENP and Aurora B kinase) and Shugoshin 1 (Sgo1) are key regulators of chromosome bi-orientation, a process essential for error-free chromosome segregation. Their functions rely on their ability to associate with centromeres. Two histone phosphorylations, histone H3 Thr3 (H3T3ph; directly recognised by Survivin) and histone H2A Thr120 (H2AT120ph; indirectly recognised via Sgo1), together with CPC’s intrinsic ability to bind nucleosome, facilitate CPC centromere recruitment. The molecular basis for CPC-Sgo1 binding and how their direct interaction influences CPC centromere localisation and function are lacking. Here, using an integrative structure-function approach, we show that the histone H3-like Sgo1 N-terminal tail interacts with Survivin acting as a hot-spot for CPC-Sgo1 assembly, while downstream Sgo1 residues, mainly with Borealin contributes for high affinity interaction. Disruption of the Sgo1 N-terminal tail-Survivin interaction abolished CPC-Sgo1 assembly in vitro and perturbed centromere localisation and function of CPC. Our findings provide evidence that CPC binding to Sgo1 and histone H3 N-terminal tail are mutually exclusive, suggesting that these interactions will likely take place in a spatially/temporally restricted manner and provide a rationale for the Sgo1-mediated ‘kinetochore proximal centromere’ pool of CPC.

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.

scholarly journals The ctf13-30/CTF13 Genomic Haploinsufficiency Modifier Screen Identifies the Yeast Chromatin Remodeling Complex RSC, Which Is Required for the Establishment of Sister Chromatid Cohesion

2004 ◽  
Vol 24 (3) ◽  
pp. 1232-1244 ◽  
Author(s):  
Kristin K. Baetz ◽  
Nevan J. Krogan ◽  
Andrew Emili ◽  
Jack Greenblatt ◽  
Philip Hieter
Keyword(s):  
Chromatin Remodeling ◽  
Chromosome Segregation ◽  
High Fidelity ◽  
Chromosome Transmission ◽  
New Genes ◽  
Sister Chromatids ◽  
Chromatin Remodeling Complex ◽  
Chromatid Cohesion ◽  
Spindle Microtubules ◽  
Mitosis And Meiosis

ABSTRACT The budding yeast centromere-kinetochore complex ensures high-fidelity chromosome segregation in mitosis and meiosis by mediating the attachment and movement of chromosomes along spindle microtubules. To identify new genes and pathways whose function impinges on chromosome transmission, we developed a genomic haploinsufficiency modifier screen and used ctf13-30, encoding a mutant core kinetochore protein, as the reference point. We demonstrate through a series of secondary screens that the genomic modifier screen is a successful method for identifying genes that encode nonessential proteins required for the fidelity of chromosome segregation. One gene isolated in our screen was RSC2, a nonessential subunit of the RSC chromatin remodeling complex. rsc2 mutants have defects in both chromosome segregation and cohesion, but the localization of kinetochore proteins to centromeres is not affected. We determined that, in the absence of RSC2, cohesin could still associate with chromosomes but fails to achieve proper cohesion between sister chromatids, indicating that RSC has a role in the establishment of cohesion. In addition, numerous subunits of RSC were affinity purified and a new component of RSC, Rtt102, was identified. Our work indicates that only a subset of the nonessential RSC subunits function in maintaining chromosome transmission fidelity.

scholarly journals Adaptive Evolution of Cid, a Centromere-Specific Histone in Drosophila

Genetics ◽  
2001 ◽  
Vol 157 (3) ◽  
pp. 1293-1298 ◽  
Author(s):  
Harmit S Malik ◽  
Steven Henikoff
Keyword(s):  
Drosophila Melanogaster ◽  
Adaptive Evolution ◽  
Chromosome Segregation ◽  
Rapid Evolution ◽  
Histone H3 ◽  
Closely Related Species ◽  
Centromeric Dna ◽  
Eukaryotic Chromosome ◽  
Histone Fold ◽  
Satellite Repeats

Abstract Centromeric DNA is generally composed of large blocks of tandem satellite repeats that change rapidly due to loss of old arrays and expansion of new repeat classes. This extreme heterogeneity of centromeric DNA is difficult to reconcile with the conservation of the eukaryotic chromosome segregation machinery. Histone H3-like proteins, including Cid in Drosophila melanogaster, are a unique chromatin component of centromeres. In comparisons between closely related species of Drosophila, we find an excess of replacement changes that have been fixed since the separation of D. melanogaster and D. simulans, suggesting adaptive evolution. The last adaptive changes appear to have occurred recently, as evident from a reduction in polymorphism in the melanogaster lineage. Adaptive evolution has occurred both in the long N-terminal tail as well as in the histone fold of Cid. In the histone fold, the replacement changes have occurred in the region proposed to mediate binding to DNA. We propose that this rapid evolution of Cid is driven by a response to the changing satellite repeats at centromeres. Thus, centromeric H3-like proteins may act as adaptors between evolutionarily labile centromeric DNA and the conserved kinetochore machinery.

scholarly journals Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Debashish U. Menon ◽  
Oleksandr Kirsanov ◽  
Christopher B. Geyer ◽  
Terry Magnuson
Keyword(s):  
Gene Ontology ◽  
Cell Division ◽  
Chromosome Segregation ◽  
Target Genes ◽  
Nuclear Division ◽  
Histone H3 ◽  
Spindle Assembly ◽  
Histone H2a ◽  
Meiotic Cell ◽  
Chromosome Passenger Complex

AbstractThe mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific subunit, in meiotic division. Arid2cKO spermatocytes arrest at metaphase-I and are deficient in spindle assembly, kinetochore-associated Polo-like kinase1 (PLK1), and centromeric targeting of Histone H3 threonine3 phosphorylation (H3T3P) and Histone H2A threonine120 phosphorylation (H2AT120P). By determining ARID2 and BRG1 genomic associations, we show that PBAF localizes to centromeres and promoters of genes known to govern spindle assembly and nuclear division in spermatocytes. Consistent with gene ontology of target genes, we also identify a role for ARID2 in centrosome stability. Additionally, misexpression of genes such as Aurkc and Ppp1cc (Pp1γ), known to govern chromosome segregation, potentially compromises the function of the chromosome passenger complex (CPC) and deposition of H3T3P, respectively. Our data support a model where-in PBAF activates genes essential for meiotic cell division.

scholarly journals CBIO-16. SUPPRESSION OF HISTONE H3.3 MITOTIC PHOSPHORYLATION DRIVES DEVELOPMENT OF H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii18-ii19
Author(s):  
Charles Day ◽  
Alyssa Langfald ◽  
Florina Grigore ◽  
Leslie Sepaniac ◽  
Jason Stumpff ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Treatment Options ◽  
Chromosome Instability ◽  
Pericentromeric Heterochromatin ◽  
Low Grade ◽  
High Grade ◽  
Chromosome Missegregation ◽  
Mitotic Phosphorylation ◽  
Chk1 Kinase

Abstract Pediatric midline gliomas – including DIPG – are lethal brain tumors in children, with poor prognosis and limited treatment options that provide only short-term benefits. The majority have a lysine-to-methionine substitution at residue 27 (H3K27M) in genes expressing histone H3 – predominantly in the H3.3 variant. This causes a global reduction in H3 Lys27 tri-methylation (H3K27Me3), comprehensive epigenetic reprogramming, and is a key driver in gliomagenesis. We show that the H3.3K27M mutation also induces chromosome segregation defects, which in high-grade tumors, results in extensive copy number alterations (CNAs). Ser31 is one of five amino acid substitutions differentiating H3.3 from canonical H3.1. Mitotic phosphorylation of H3.3 Ser31 by Chk1 kinase is restricted to pericentromeric heterochromatin, where it plays a role in chromosome segregation. We show that the K27M mutation affects neighboring Ser31 phosphorylation and pericentromeric heterochromatin organization. We demonstrate that (i) H3.3 K27M protein is defective for Ser31 phosphorylation by Chk1 kinase in vitro; (ii) DIPG cell lines have significantly decreased mitotic Ser31 phosphorylation, and are chromosomally unstable; and (iii) CRISPR-reversion of H3.3K27M to Lys27 restores phospho-Ser31 (and Lys27 tri-methylation) and significantly decreases chromosome instability. Expression of H3.3K27M or non-phosphorylatable H3.3S31A mutants in WT cells results in chromosome missegregation; this is suppressed by co-expression of phospho-mimetic H3.3K27M/S31E. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. Finally, in a novel mouse model of glioma, mean survival of mice with tumors induced with H3.3K27M and H3.3S31A was 81 and 68 days: 100% of H3.3S31A mice developed high-grade tumors. H3.3 WT controls developed only low-grade tumors and all survived 100 days. H3.3S31A is WT for Lys27 tri-methylation and thus, loss of Ser31 phosphorylation alone is oncogenic.

scholarly journals A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans

PLoS Biology ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. e3000331 ◽  
Author(s):  
Cedric A. Brimacombe ◽  
Jordan E. Burke ◽  
Jahan-Yar Parsa ◽  
Sandra Catania ◽  
Teresa R. O’Meara ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Phosphorylation Site ◽  
Histone H2a
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