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Science (New York, N.Y.) Nov 2021Centromeres attach chromosomes to spindle microtubules during cell division and, despite this conserved role, show paradoxically rapid evolution and are typified by...
Centromeres attach chromosomes to spindle microtubules during cell division and, despite this conserved role, show paradoxically rapid evolution and are typified by complex repeats. We used long-read sequencing to generate the Col-CEN genome assembly that resolves all five centromeres. The centromeres consist of megabase-scale tandemly repeated satellite arrays, which support CENTROMERE SPECIFIC HISTONE H3 (CENH3) occupancy and are densely DNA methylated, with satellite variants private to each chromosome. CENH3 preferentially occupies satellites that show the least amount of divergence and occur in higher-order repeats. The centromeres are invaded by retrotransposons, which disrupt genetic and epigenetic organization. Centromeric crossover recombination is suppressed, yet low levels of meiotic DNA double-strand breaks occur that are regulated by DNA methylation. We propose that centromeres are evolving through cycles of satellite homogenization and retrotransposon-driven diversification.
Topics: Arabidopsis; Centromere; Chromosomes, Plant; DNA Methylation; DNA, Satellite; Epigenesis, Genetic; Evolution, Molecular; Genome, Plant; Histones; Meiosis; Recombination, Genetic; Retroelements; Sequence Analysis, DNA
PubMed: 34762468
DOI: 10.1126/science.abi7489 -
Current Biology : CB Jun 2016Centromeres, chromosomal regions that become physically linked to the spindle during cell division, ensure equal division of genetic material between daughter cells....
Centromeres, chromosomal regions that become physically linked to the spindle during cell division, ensure equal division of genetic material between daughter cells. They are ubiquitous and essential in eukaryotic life. In this primer, we ask the questions 'What defines a functional centromere?' and 'What do all centromeres have in common?' To address these questions we highlight what is known about centromere size, centromere architecture, underlying DNA sequence and centromeric proteins. Studies from a variety of organisms reveal a vast diversity in centromere form and function that remains perplexing and largely unexplained.
Topics: Animals; Centromere; Humans; Saccharomycetales
PubMed: 27326706
DOI: 10.1016/j.cub.2016.05.031 -
Nature Structural & Molecular Biology Jun 2023In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. The protection of centromeric cohesin by SGO1 maintains the sister...
In the early stages of mitosis, cohesin is released from chromosome arms but not from centromeres. The protection of centromeric cohesin by SGO1 maintains the sister chromatid cohesion that resists the pulling forces of microtubules until all chromosomes are attached in a bipolar manner to the mitotic spindle. Here we present the X-ray crystal structure of a segment of human SGO1 bound to a conserved surface of the cohesin complex. SGO1 binds to a composite interface formed by the SA2 and SCC1 subunits of cohesin. SGO1 shares this binding interface with CTCF, indicating that these distinct chromosomal regulators control cohesin through a universal principle. This interaction is essential for the localization of SGO1 to centromeres and protects centromeric cohesin against WAPL-mediated cohesin release. SGO1-cohesin binding is maintained until the formation of microtubule-kinetochore attachments and is required for faithful chromosome segregation and the maintenance of a stable karyotype.
Topics: Humans; HeLa Cells; Centromere; Cell Cycle Proteins; Kinetochores; Mitosis; Chromosome Segregation; Chromatids
PubMed: 37081319
DOI: 10.1038/s41594-023-00968-y -
Chromosome Research : An International... Sep 2022Centromeres connect chromosomes and spindle microtubules to ensure faithful chromosome segregation. Paradoxically, despite this conserved function, centromeric DNA... (Review)
Review
Centromeres connect chromosomes and spindle microtubules to ensure faithful chromosome segregation. Paradoxically, despite this conserved function, centromeric DNA evolves rapidly and centromeric proteins show signatures of positive selection. The centromere drive hypothesis proposes that centromeric DNA can act like a selfish genetic element and drive non-Mendelian segregation during asymmetric female meiosis. Resulting fitness costs lead to genetic conflict with the rest of the genome and impose a selective pressure for centromeric proteins to adapt by suppressing the costs. Here, we describe experimental model systems for centromere drive in yellow monkeyflowers and mice, summarize key findings demonstrating centromere drive, and explain molecular mechanisms. We further discuss efforts to test if centromeric proteins are involved in suppressing drive-associated fitness costs, highlight a model for centromere drive and suppression in mice, and put forth outstanding questions for future research.
Topics: Animals; Centromere; Chromosome Segregation; DNA; Female; Meiosis; Mice; Microtubules
PubMed: 35731424
DOI: 10.1007/s10577-022-09696-3 -
Molecular Biology and Evolution Aug 2022Centromeres are epigenetically specified by the histone H3 variant CENP-A and typically associated with highly repetitive satellite DNA. We previously discovered natural...
Centromeres are epigenetically specified by the histone H3 variant CENP-A and typically associated with highly repetitive satellite DNA. We previously discovered natural satellite-free neocentromeres in Equus caballus and Equus asinus. Here, through ChIP-seq with an anti-CENP-A antibody, we found an extraordinarily high number of centromeres lacking satellite DNA in the zebras Equus burchelli (15 of 22) and Equus grevyi (13 of 23), demonstrating that the absence of satellite DNA at the majority of centromeres is compatible with genome stability and species survival and challenging the role of satellite DNA in centromere function. Nine satellite-free centromeres are shared between the two species in agreement with their recent separation. We assembled all centromeric regions and improved the reference genome of E. burchelli. Sequence analysis of the CENP-A binding domains revealed that they are LINE-1 and AT-rich with four of them showing DNA amplification. In the two zebras, satellite-free centromeres emerged from centromere repositioning or following Robertsonian fusion. In five chromosomes, the centromeric function arose near the fusion points, which are located within regions marked by traces of ancestral pericentromeric sequences. Therefore, besides centromere repositioning, Robertsonian fusions are an important source of satellite-free centromeres during evolution. Finally, in one case, a satellite-free centromere was seeded on an inversion breakpoint. At 11 chromosomes, whose primary constrictions seemed to be associated with satellite repeats by cytogenetic analysis, satellite-free neocentromeres were instead located near the ancestral inactivated satellite-based centromeres; therefore, the centromeric function has shifted away from a satellite repeat containing locus to a satellite-free new position.
Topics: Animals; Centromere; Centromere Protein A; DNA, Satellite; Histones; Horses
PubMed: 35881460
DOI: 10.1093/molbev/msac162 -
Molecular Cell Feb 2023Centromeres are essential for chromosome segregation in most animals and plants yet are among the most rapidly evolving genome elements. The mechanisms underlying this...
Centromeres are essential for chromosome segregation in most animals and plants yet are among the most rapidly evolving genome elements. The mechanisms underlying this paradoxical phenomenon remain enigmatic. Here, we report that human centromeres innately harbor a striking enrichment of DNA breaks within functionally active centromere regions. Establishing a single-cell imaging strategy that enables comparative assessment of DNA breaks at repetitive regions, we show that centromeric DNA breaks are induced not only during active cellular proliferation but also de novo during quiescence. Markedly, centromere DNA breaks in quiescent cells are resolved enzymatically by the evolutionarily conserved RAD51 recombinase, which in turn safeguards the specification of functional centromeres. This study highlights the innate fragility of centromeres, which may have been co-opted over time to reinforce centromere specification while driving rapid evolution. The findings also provide insights into how fragile centromeres are likely to contribute to human disease.
Topics: Animals; Humans; Centromere; DNA; Centromere Protein A; Rad51 Recombinase; Recombination, Genetic
PubMed: 36702125
DOI: 10.1016/j.molcel.2023.01.004 -
Chromosoma Oct 2017The centromere directs chromosome segregation and genetic inheritance but is not itself heritable in a canonical, DNA-based manner. In most species, centromeres are... (Review)
Review
The centromere directs chromosome segregation and genetic inheritance but is not itself heritable in a canonical, DNA-based manner. In most species, centromeres are epigenetically defined by the presence of a histone H3 variant centromere protein A (CENP-A), independent of underlying DNA sequence. Therefore, centromere inheritance depends on maintaining the CENP-A nucleosome mark across generations. Experiments in cycling somatic cells have led to a model in which centromere identity is maintained by a cell cycle-coupled CENP-A chromatin assembly pathway. However, the processes of animal gametogenesis pose unique challenges to centromere inheritance because of the extended cell cycle arrest and the massive genome reorganization in the female and male germline, respectively. Here, we review our current understanding of germline centromere inheritance and highlight outstanding questions.
Topics: Animals; Centromere; Centromere Protein A; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Germ Cells; Humans; Inheritance Patterns
PubMed: 28791511
DOI: 10.1007/s00412-017-0640-y -
Progress in Molecular and Subcellular... 2017The centromere is the genetic locus that specifies the site of kinetochore assembly, where the chromosome will attach to the kinetochore microtubule. The pericentromere... (Review)
Review
The centromere is the genetic locus that specifies the site of kinetochore assembly, where the chromosome will attach to the kinetochore microtubule. The pericentromere is the physical region responsible for the geometry of bi-oriented sister kinetochores in metaphase. In budding yeast the 125 bp point centromere is sufficient to specify kinetochore assembly. The flanking region is enriched (3X) in cohesin and condensin relative to the remaining chromosome arms. The enrichment spans about 30-50 kb around each centromere. We refer to the flanking chromatin as the pericentromere in yeast. In mammals, a 5-10 Mb region dictates where the kinetochore is built. The kinetochore interacts with a very small fraction of DNA on the surface of the centromeric region. The remainder of the centromere lies between the sister kinetochores. This is typically called centromere chromatin. The chromatin sites that directly interface to microtubules cannot be identified due to the repeated sequence within the mammalian centromere. However in both yeast and mammals, the total amount of DNA between the sites of microtubule attachment in metaphase is highly conserved. In yeast the 16 chromosomes are clustered into a 250 nm diameter region, and 800 kb (16 × 50 kb) or ~1 Mb of DNA lies between sister kinetochores. In mammals, 5-10 Mb lies between sister kinetochores. In both organisms the sister kinetochores are separated by about 1 μm. Thus, centromeres of different organisms differ in how they specify kinetochore assembly, but there may be important centromere chromatin functions that are conserved throughout phylogeny. Recently, centromeric chromatin has been reconstituted in vitro using alpha satellite DNA revealing unexpected features of centromeric DNA organization, replication, and response to stress. We will focus on the conserved features of centromere in this review.
Topics: Animals; Centromere; Chromatin; Kinetochores; Microtubules; Saccharomyces cerevisiae
PubMed: 28840251
DOI: 10.1007/978-3-319-58592-5_21 -
Current Opinion in Genetics &... Dec 2022Centromeres are essential loci in eukaryotes that are necessary for the faithful segregation of chromosomes in mitosis and meiosis. Centromeres organize the kinetochore,... (Review)
Review
Centromeres are essential loci in eukaryotes that are necessary for the faithful segregation of chromosomes in mitosis and meiosis. Centromeres organize the kinetochore, the protein machine that attaches sister chromatids or homologous chromosomes to spindle microtubules and regulates their disjunction. Centromeres have both genetic and epigenetic determinants, which can come into conflict in asymmetric female meiosis in seed plants and animals. The centromere drive model was proposed to describe this conflict and explain how it leads to the rapid evolution of both centromeres and kinetochores. Recent studies confirm key aspects of the centromere drive model, clarify its mechanisms, and implicate rapid centromere/kinetochore evolution in hybrid inviability between species.
Topics: Animals; Chromatin; Chromosome Segregation; Centromere; Kinetochores; Meiosis; Mitosis
PubMed: 36372007
DOI: 10.1016/j.gde.2022.102005 -
Biomolecules Dec 2023Centromeres play essential roles in the faithful segregation of chromosomes. CENP-A, the centromere-specific histone H3 variant, and heterochromatin characterized by di-... (Review)
Review
Centromeres play essential roles in the faithful segregation of chromosomes. CENP-A, the centromere-specific histone H3 variant, and heterochromatin characterized by di- or tri-methylation of histone H3 9th lysine (H3K9) are the hallmarks of centromere chromatin. Contrary to the epigenetic marks, DNA sequences underlying the centromere region of chromosomes are not well conserved through evolution. However, centromeres consist of repetitive sequences in many eukaryotes, including animals, plants, and a subset of fungi, including fission yeast. Advances in long-read sequencing techniques have uncovered the complete sequence of human centromeres containing more than thousands of alpha satellite repeats and other types of repetitive sequences. Not only tandem but also inverted repeats are present at a centromere. DNA recombination between centromere repeats can result in gross chromosomal rearrangement (GCR), such as translocation and isochromosome formation. CENP-A chromatin and heterochromatin suppress the centromeric GCR. The key player of homologous recombination, Rad51, safeguards centromere integrity through conservative noncrossover recombination between centromere repeats. In contrast to Rad51-dependent recombination, Rad52-mediated single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) lead to centromeric GCR. This review summarizes recent findings on the role of centromere and recombination proteins in maintaining centromere integrity and discusses how GCR occurs at centromeres.
Topics: Animals; Humans; Histones; Centromere Protein A; Heterochromatin; Centromere; Chromosome Aberrations; Chromatin
PubMed: 38254628
DOI: 10.3390/biom14010028