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Cold Spring Harbor Perspectives in... May 2015Recombination is a prominent feature of meiosis in which it plays an important role in increasing genetic diversity during inheritance. Additionally, in most organisms,... (Review)
Review
Recombination is a prominent feature of meiosis in which it plays an important role in increasing genetic diversity during inheritance. Additionally, in most organisms, recombination also plays mechanical roles in chromosomal processes, most notably to mediate pairing of homologous chromosomes during prophase and, ultimately, to ensure regular segregation of homologous chromosomes when they separate at the first meiotic division. Recombinational interactions are also subject to important spatial patterning at both early and late stages. Recombination-mediated processes occur in physical and functional linkage with meiotic axial chromosome structure, with interplay in both directions, before, during, and after formation and dissolution of the synaptonemal complex (SC), a highly conserved meiosis-specific structure that links homolog axes along their lengths. These diverse processes also are integrated with recombination-independent interactions between homologous chromosomes, nonhomology-based chromosome couplings/clusterings, and diverse types of chromosome movement. This review provides an overview of these diverse processes and their interrelationships.
Topics: Animals; Chromosome Pairing; Chromosomes; DNA Breaks, Double-Stranded; Humans; Meiosis; Recombination, Genetic; Synaptonemal Complex
PubMed: 25986558
DOI: 10.1101/cshperspect.a016626 -
Nature Jul 2017Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that...
Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of cis-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.
Topics: Animals; Cell Compartmentation; Cell Cycle; Chromosomes, Mammalian; Epigenesis, Genetic; Haploidy; Imaging, Three-Dimensional; Mice; Mouse Embryonic Stem Cells; Reproducibility of Results; Single-Cell Analysis
PubMed: 28682332
DOI: 10.1038/nature23001 -
Nature Jun 2023Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s), is an ubiquitous mutational process generating localized and complex chromosomal...
Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s), is an ubiquitous mutational process generating localized and complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by mis-segregation errors in mitosis or DNA metabolism that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or following mitotic entry. Here we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of mediator of DNA damage checkpoint 1 (MDC1), DNA topoisomerase II-binding protein 1 (TOPBP1) and cellular inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome mis-segregation and shattering after transient inactivation of the spindle assembly checkpoint. Transient, degron-induced reduction in CIP2A following chromosome micronucleation-dependent chromosome shattering is shown to drive acquisition of segmental deletions and inversions. Analyses of pancancer tumour genomes showed that expression of CIP2A and TOPBP1 was increased overall in cancers with genomic rearrangements, including copy number-neutral chromothripsis with minimal deletions, but comparatively reduced in cancers with canonical chromothripsis in which deletions were frequent. Thus, chromatin-bound tethers maintain the proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.
Topics: Humans; Cell Nucleus; Chromosome Segregation; Chromosomes, Human; Chromothripsis; Mitosis; Neoplasms; Chromatin
PubMed: 37316668
DOI: 10.1038/s41586-023-06216-z -
Nature Genetics Dec 2022In mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown...
In mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions.
Topics: Chromosomes
PubMed: 36471076
DOI: 10.1038/s41588-022-01232-7 -
PLoS Genetics Jul 2020Holocentric chromosomes possess multiple kinetochores along their length rather than the single centromere typical of other chromosomes [1]. They have been described for...
Holocentric chromosomes possess multiple kinetochores along their length rather than the single centromere typical of other chromosomes [1]. They have been described for the first time in cytogenetic experiments dating from 1935 and, since this first observation, the term holocentric chromosome has referred to chromosomes that: i. lack the primary constriction corresponding to centromere observed in monocentric chromosomes [2]; ii. possess multiple kinetochores dispersed along the chromosomal axis so that microtubules bind to chromosomes along their entire length and move broadside to the pole from the metaphase plate [3]. These chromosomes are also termed holokinetic, because, during cell division, chromatids move apart in parallel and do not form the classical V-shaped figures typical of monocentric chromosomes [4-6]. Holocentric chromosomes evolved several times during both animal and plant evolution and are currently reported in about eight hundred diverse species, including plants, insects, arachnids and nematodes [7,8]. As a consequence of their diffuse kinetochores, holocentric chromosomes may stabilize chromosomal fragments favouring karyotype rearrangements [9,10]. However, holocentric chromosome may also present limitations to crossing over causing a restriction of the number of chiasma in bivalents [11] and may cause a restructuring of meiotic divisions resulting in an inverted meiosis [12].
Topics: Animals; Caenorhabditis elegans; Centromere; Chromatids; Chromosome Segregation; Chromosomes; Karyotype; Kinetochores; Meiosis; Plants
PubMed: 32730246
DOI: 10.1371/journal.pgen.1008918 -
Annual Review of Biochemistry Jun 2023SMC (structural maintenance of chromosomes) protein complexes are an evolutionarily conserved family of motor proteins that hold sister chromatids together and fold... (Review)
Review
SMC (structural maintenance of chromosomes) protein complexes are an evolutionarily conserved family of motor proteins that hold sister chromatids together and fold genomes throughout the cell cycle by DNA loop extrusion. These complexes play a key role in a variety of functions in the packaging and regulation of chromosomes, and they have been intensely studied in recent years. Despite their importance, the detailed molecular mechanism for DNA loop extrusion by SMC complexes remains unresolved. Here, we describe the roles of SMCs in chromosome biology and particularly review in vitro single-molecule studies that have recently advanced our understanding of SMC proteins. We describe the mechanistic biophysical aspects of loop extrusion that govern genome organization and its consequences.
Topics: Chromosomal Proteins, Non-Histone; Multiprotein Complexes; Chromosomes; DNA; Cell Cycle Proteins
PubMed: 37137166
DOI: 10.1146/annurev-biochem-032620-110506 -
Philosophical Transactions of the Royal... Feb 2000B chromosomes are extra chromosomes to the standard complement that occur in many organisms. They can originate in a number of ways including derivation from autosomes... (Review)
Review
B chromosomes are extra chromosomes to the standard complement that occur in many organisms. They can originate in a number of ways including derivation from autosomes and sex chromosomes in intra- and interspecies crosses. Their subsequent molecular evolution resembles that of univalent sex chromosomes, which involves gene silencing, heterochromatinization and the accumulation of repetitive DNA and transposons. B-chromosome frequencies in populations result from a balance between their transmission rates and their effects on host fitness. Their long-term evolution is considered to be the outcome of selection on the host genome to eliminate B chromosomes or suppress their effects and on the B chromosome's ability to escape through the generation of new variants. Because B chromosomes interact with the standard chromosomes, they can play an important role in genome evolution and may be useful for studying molecular evolutionary processes.
Topics: Animals; Biological Evolution; Chromosomes; Genetic Variation
PubMed: 10724453
DOI: 10.1098/rstb.2000.0556 -
Cytogenetic and Genome Research 2013In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in... (Review)
Review
In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in fishes ranges from 2 to 25 kb and shortens with age in some of the species. To date, chromosomal distribution of the telomeric DNA sequences has been examined in approximately 80 fish species of which about 42% show additional telomeric hybridization signals far from the chromosomal termini. Based on the chromosomal location, such internally located telomeric repeats may be classified into 4 categories: (1) telomeric DNA sequences located at the pericentromeric regions, (2) interstitial telomeric sites observed between centromeres and the bona fide telomeres, (3) telomeric DNA sequences that scatter along the nucleolus organizer regions, and (4) telomeric DNA repeats interspersed with the entire chromosomes. Most of the pericentromeric and interstitial telomeric sequences in fish are possible relicts of chromosome fusion events. The origin of the telomeric sequences co- localizing with the major rDNA sequences or scattered along the whole chromosomes is not clear. Internally located telomeric repeats are considered as 'hot spots' for recombination and thus may potentially increase the rates of chromosome breaks and rearrangements leading to the various chromosomal polymorphisms in fishes. FISH with telomeric probe applied to metaphase spreads of androgenetic specimens that hatched from eggs exposed to ionizing radiation before insemination enabled the detection of small radiation-induced fragments of maternal chromosomes. Remnants of the irradiated chromosomes were found to be ring chromosomes with the interstitial telomeric signals, telomerless rings, fragments with fused sister chromatids, and linear fragments with telomeres detected at both of their ends. The increasing availability of techniques enabling the study of fish telomeres and telomerase and the easy access to numerous fish species strongly confirm that these animals are promising models in research concerning the role of telomeres and telomerase in vertebrate aging, repair of ionizing radiation-induced DNA double strand breaks, and chromosomal rearrangements.
Topics: Animals; Base Sequence; Chromosomes; DNA Damage; Fishes; Humans; Telomere
PubMed: 23988378
DOI: 10.1159/000354278 -
International Journal of Molecular... Feb 2019The concept of "chromosomics" was introduced by Prof. Uwe Claussen in 2005. Herein, the growing insights into human chromosome structure finally lead to a "chromosomic... (Review)
Review
BACKGROUND
The concept of "chromosomics" was introduced by Prof. Uwe Claussen in 2005. Herein, the growing insights into human chromosome structure finally lead to a "chromosomic view" of the three-dimensional constitution and plasticity of genes in interphase nuclei are discussed. This review is dedicated to the memory of Prof. Uwe Claussen (30 April 1945⁻20 July 2008).
RECENT FINDINGS
Chromosomics is the study of chromosomes, their three-dimensional positioning in the interphase nucleus, the consequences from plasticity of chromosomal subregions and gene interactions, the influence of chromatin-modification-mediated events on cells, and even individuals, evolution, and disease. Progress achieved in recent years is summarized, including the detection of chromosome-chromosome-interactions which, if damaged, lead to malfunction and disease. However, chromosomics in the Human Genetics field is not progressing presently, as research interest has shifted from single cell to high throughput, genomic approaches.
CONCLUSION
Chromosomics and its impact were predicted correctly in 2005 by Prof. Claussen. Although some progress was achieved, present reconsiderations of the role of the chromosome and the single cell in Human Genetic research are urgently necessary.
Topics: Cell Nucleus; Chromosomes, Human; Cytogenetics; Genome, Human; Genomics; Humans
PubMed: 30769866
DOI: 10.3390/ijms20040826 -
Experimental Cell Research May 2020"Genomically" humanized animals are invaluable tools for generating human disease models and for biomedical research. Humanized animal models have generally been... (Review)
Review
"Genomically" humanized animals are invaluable tools for generating human disease models and for biomedical research. Humanized animal models have generally been developed via conventional transgenic technologies; however, conventional gene delivery vectors such as viruses, plasmids, bacterial artificial chromosomes, P1 phase-derived artificial chromosomes, and yeast artificial chromosomes have limitations for transgenic animal creation as their loading gene capacity is restricted, and the expression of transgenes is unstable. Transchromosomic (Tc) techniques using mammalian artificial chromosomes, including human chromosome fragments, human artificial chromosomes, and mouse artificial chromosomes, have overcome these limitations. These tools can carry multiple genes or Mb-sized genomic loci and their associated regulatory elements, which has facilitated the creation of more useful and complex transgenic models for human disease, drug development, and humanized animal research. This review describes the history of Tc animal development, the applications of Tc animals, and future prospects.
Topics: Aneuploidy; Animals; Animals, Genetically Modified; Cattle; Chromosomes, Artificial, Mammalian; Chromosomes, Human; Gene Editing; Gene Transfer Techniques; Goats; Humans; Mice; Plasmids; Rats
PubMed: 32142854
DOI: 10.1016/j.yexcr.2020.111914