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Cells Jan 2019Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten... (Review)
Review
Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.
Topics: Aging; DNA Replication; Homeostasis; Humans; Phenotype; Telomere; Telomere Homeostasis
PubMed: 30669451
DOI: 10.3390/cells8010073 -
Genes & Development Sep 2005Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and... (Review)
Review
Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.
Topics: Antigens, Surface; Binding Sites; Cell Adhesion Molecules; Chromosomal Instability; DNA Damage; Humans; Membrane Glycoproteins; Models, Biological; Multiprotein Complexes; Peptide Hydrolases; Protein Binding; Protein Structure, Tertiary; Protein Subunits; Proteins; Shelterin Complex; Tandem Repeat Sequences; Telomere; Telomere-Binding Proteins; Telomeric Repeat Binding Protein 1; Telomeric Repeat Binding Protein 2; rap1 GTP-Binding Proteins
PubMed: 16166375
DOI: 10.1101/gad.1346005 -
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 -
Molecular Cell Nov 2019Eukaryotic chromosomes contain compartments of various functions, which are marked by and enriched with specific histone modifications. However, the molecular mechanisms...
Eukaryotic chromosomes contain compartments of various functions, which are marked by and enriched with specific histone modifications. However, the molecular mechanisms by which these histone marks function in chromosome compartmentalization are poorly understood. Constitutive heterochromatin is a largely silent chromosome compartment characterized in part by H3K9me2 and 3. Here, we show that heterochromatin protein 1 (HP1), an H3K9me2 and 3 "reader," interacts with SUV39H1, an H3K9me2 and 3 "writer," and with TRIM28, an abundant HP1 scaffolding protein, to form complexes with increased multivalent engagement of H3K9me2 and 3-modified chromatin. H3K9me2 and 3-marked nucleosomal arrays and associated complexes undergo phase separation to form macromolecule-enriched liquid droplets. The droplets are reminiscent of heterochromatin as they are highly dense chromatin-containing structures that are resistant to DNase and exclude the general transcription factor TFIIB. Our data suggest a general mechanism by which histone marks regulate chromosome compartmentalization by promoting phase separation.
Topics: Chromatin Assembly and Disassembly; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone; HEK293 Cells; Heterochromatin; Histones; Humans; Lipid Droplets; Methylation; Methyltransferases; Multiprotein Complexes; Nucleosomes; Protein Processing, Post-Translational; Repressor Proteins; Time Factors; Tripartite Motif-Containing Protein 28
PubMed: 31543422
DOI: 10.1016/j.molcel.2019.08.019 -
Science China. Life Sciences May 2012Archaea, along with Bacteria and Eukarya, are the three domains of life. In all living cells, chromatin proteins serve a crucial role in maintaining the integrity of the... (Review)
Review
Archaea, along with Bacteria and Eukarya, are the three domains of life. In all living cells, chromatin proteins serve a crucial role in maintaining the integrity of the structure and function of the genome. An array of small, abundant and basic DNA-binding proteins, considered candidates for chromatin proteins, has been isolated from the Euryarchaeota and the Crenarchaeota, the two major phyla in Archaea. While most euryarchaea encode proteins resembling eukaryotic histones, crenarchaea appear to synthesize a number of unique DNA-binding proteins likely involved in chromosomal organization. Several of these proteins (e.g., archaeal histones, Sac10b homologs, Sul7d, Cren7, CC1, etc.) have been extensively studied. However, whether they are chromatin proteins and how they function in vivo remain to be fully understood. Future investigation of archaeal chromatin proteins will lead to a better understanding of chromosomal organization and gene expression in Archaea and provide valuable information on the evolution of DNA packaging in cellular life.
Topics: Amino Acid Sequence; Archaeal Proteins; Chromatin; Models, Molecular; Molecular Sequence Data; Phylogeny; Sequence Homology, Amino Acid
PubMed: 22645082
DOI: 10.1007/s11427-012-4322-y -
Genes Nov 2019Repetitive DNAs are ubiquitous in eukaryotic genomes and, in many species, comprise the bulk of the genome. Repeats include transposable elements that can self-mobilize...
Repetitive DNAs are ubiquitous in eukaryotic genomes and, in many species, comprise the bulk of the genome. Repeats include transposable elements that can self-mobilize and disperse around the genome and tandemly-repeated satellite DNAs that increase in copy number due to replication slippage and unequal crossing over. Despite their abundance, repetitive DNAs are often ignored in genomic studies due to technical challenges in identifying, assembling, and quantifying them. New technologies and methods are now allowing unprecedented power to analyze repetitive DNAs across diverse taxa. Repetitive DNAs are of particular interest because they can represent distinct modes of genome evolution. Some repetitive DNAs form essential genome structures, such as telomeres and centromeres, that are required for proper chromosome maintenance and segregation, while others form piRNA clusters that regulate transposable elements; thus, these elements are expected to evolve under purifying selection. In contrast, other repeats evolve selfishly and cause genetic conflicts with their host species that drive adaptive evolution of host defense systems. However, the majority of repeats likely accumulate in eukaryotes in the absence of selection due to mechanisms of transposition and unequal crossing over. However, even these "neutral" repeats may indirectly influence genome evolution as they reach high abundance. In this Special Issue, the contributing authors explore these questions from a range of perspectives.
Topics: Animals; Centromere; DNA Transposable Elements; DNA, Satellite; Evolution, Molecular; Genome; Genomics; Heterochromatin; Humans; Repetitive Sequences, Nucleic Acid; Telomere
PubMed: 31698818
DOI: 10.3390/genes10110896 -
Cell Biology and Toxicology Oct 2018Genome is a complex hierarchical structure, and its spatial organization plays an important role in its function. Chromatin loops and topological domains form the basic... (Review)
Review
Genome is a complex hierarchical structure, and its spatial organization plays an important role in its function. Chromatin loops and topological domains form the basic structural units of this multiscale organization and are essential to orchestrate complex regulatory networks and transcription mechanisms. They also form higher-order structures such as chromosomal compartments and chromosome territories. Each level of this intrinsic architecture is governed by principles and mechanisms that we only start to understand. In this review, we summarize the current view of the genome architecture on the scales ranging from chromatin loops to the whole genome. We describe cell-to-cell variability, links between genome reorganization and various genomic processes, such as chromosome X inactivation and cell differentiation, and the interplay between different experimental techniques.
Topics: Chromatin; Chromosome Structures; Chromosomes; Computational Biology; DNA; Genome; Humans; Imaging, Three-Dimensional; Sequence Analysis, DNA
PubMed: 29568981
DOI: 10.1007/s10565-018-9428-y -
Results and Problems in Cell... 2022Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads... (Review)
Review
Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads to almost inert chromatin, with the impossibility of conducting gene transcription as in most other somatic cells. The major chromosomal structure responsible for DNA condensation is the formation of protamine-DNA toroids containing 25-50 kilobases of DNA. These toroids are connected by toroid linker regions (TLR), which attach them to the nuclear matrix, as matrix attachment regions (MAR) do in somatic cells. Despite this high degree of condensation, evidence shows that sperm chromatin contains vulnerable elements that can be degraded even in fully condensed chromatin, which may correspond to chromatin regions that transfer functionality to the zygote at fertilization. This chapter covers an updated review of our model for sperm chromatin structure and its potential functional elements that affect embryo development.
Topics: Male; Humans; Semen; Chromatin; Spermatozoa; Protamines; DNA
PubMed: 36348112
DOI: 10.1007/978-3-031-06573-6_10 -
Pharmacology & Therapeutics Apr 2021The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter... (Review)
Review
The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.
Topics: DNA; Humans; Occupational Health; Shelterin Complex; Telomere; Telomere Homeostasis; Telomere-Binding Proteins; Toxicology
PubMed: 33176178
DOI: 10.1016/j.pharmthera.2020.107742 -
Cellular and Molecular Life Sciences :... Feb 2024Cell division is a crucial process, and one of its essential steps involves copying the genetic material, which is organized into structures called chromosomes. Before a... (Review)
Review
Cell division is a crucial process, and one of its essential steps involves copying the genetic material, which is organized into structures called chromosomes. Before a cell can divide into two, it needs to ensure that each newly copied chromosome is paired tightly with its identical twin. This pairing is maintained by a protein complex known as cohesin, which is conserved in various organisms, from single-celled ones to humans. Cohesin essentially encircles the DNA, creating a ring-like structure to handcuff, to keep the newly synthesized sister chromosomes together in pairs. Therefore, chromosomal cohesion and separation are fundamental processes governing the attachment and segregation of sister chromatids during cell division. Metaphase-to-anaphase transition requires dissolution of cohesins by the enzyme Separase. The tight regulation of these processes is vital for safeguarding genomic stability. Dysregulation in chromosomal cohesion and separation resulting in aneuploidy, a condition characterized by an abnormal chromosome count in a cell, is strongly associated with cancer. Aneuploidy is a recurring hallmark in many cancer types, and abnormalities in chromosomal cohesion and separation have been identified as significant contributors to various cancers, such as acute myeloid leukemia, myelodysplastic syndrome, colorectal, bladder, and other solid cancers. Mutations within the cohesin complex have been associated with these cancers, as they interfere with chromosomal segregation, genome organization, and gene expression, promoting aneuploidy and contributing to the initiation of malignancy. In summary, chromosomal cohesion and separation processes play a pivotal role in preserving genomic stability, and aberrations in these mechanisms can lead to aneuploidy and cancer. Gaining a deeper understanding of the molecular intricacies of chromosomal cohesion and separation offers promising prospects for the development of innovative therapeutic approaches in the battle against cancer.
Topics: Humans; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Cohesins; Chromatids; Carcinogenesis; Cell Transformation, Neoplastic; Neoplasms; Chromosome Segregation; Aneuploidy; Genomic Instability
PubMed: 38388697
DOI: 10.1007/s00018-024-05122-5