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Dicentric chromosomes and chromosome instability. Representation of the possible origins of dicentric chromosomes that arise from chromosome/ telomere fusions or neocentromere formation in the presence of a functional original centromere. During anaphase onset, the dicentric chromosome that is attached by opposing mitotic spindle fibers is trapped, leading to anaphase and chromosome bridges and, consequently, DNA damage and chromosome instability. Centromere inactivation could restore faithful segregation by preventing incorrect spindle attachment
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Centromeres are the chromosomal domains required to ensure faithful transmission of the genome during cell division. They have a central role in preventing aneuploidy, by orchestrating the assembly of several components required for chromosome separation. However, centromeres also adopt a complex structure that makes them susceptible to being sites...
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... described in maize by Barbara McClintock as the result of a type of crossing over between a broken chromosome and its normal homolog 136 . Indeed, it is believed that dicentric chromosomes arise after double-strand break formation leading to inversions and translocations or chromosome fusion via telomere deprotection (reviewed in ref. 137 ) (Fig. 4). In the case of chromosome rearrangements, a physical breakage of two chromosomes, homologs or not, can produce sticky ends that recombine end to end (inversion) gen- erating one dicentric chromosome and two acentric fragments (one in the case of reciprocal translocation). Telomere shortening (e.g. during aging) or dysfunctional ...
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... by telomere HR and centromere silencing via active transcription 141 were shown to attach to opposite mitotic spindle poles. Simultaneous pulling towards the opposite poles led to the formation of anaphase bridges 142 . Subsequently, dicentric chromosomes are broken at mitotic exit during cytokinesis in an actin filament-dependent mechanism (Fig. 4). The breakage site normally corresponds to the telomere fusion site in the case of dicentrics formed through telomere deprotection 143 or to pericentromeric regions within a 25-30 kb range if the dicentric chromosome formation did not involve telomere fusion 142 . On the contrary, about 50% of dicentric chromosomes induced in human ...
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... such as TREX1. Nuclease activity led to ssDNA formation (indeed, 80% of these chromatin bridges accumulated RPA) favoring DNA repair and APOBEC-mediated editing of the fragmented chromatin bridge DNA. This chromatin fragmentation and repair was shown to generate chromothripsis and Kataegis (clusters of closely localized base substitutions) 145 (Fig. ...
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... chromosomes. Dicentric chromosomes are generally unstable (especially when generated experimentally), however there are cases of stable dicentric chromosomes, namely pseudodicentric chromosomes (Fig. 4). Their stability is conferred either by deletion of centromeric DNA sequence 144 or (mostly) by epigenetic inactivation of one of the two centromeres, causing loss of centromeric components such as CENP-A and CENP- C 147,148 . An example of pseudodicentric chromosomes are those formed via Robertsonian translocations (ROBs) (Fig. 1). ...
Citations
... The centromere is the primary constriction of mitotic chromosomes and a platform for kinetochore formation and spindle attachment (Westhorpe and Straight, 2014). Defects in centromere formation result in aberrant chromosome segregation, micronuclei formation, and chromosomal defects (Barra and Fachinetti, 2018). However, our understanding of the mechanisms ensuring faithful centromere formation across cell types remains limited. ...
The centromere is a fundamental higher-order structure in chromosomes ensuring their faithful segregation upon cell division. Centromeric transcripts have been described in several species and suggested to participate in centromere function. However, low sequence conservation of centromeric repeats appears inconsistent with a role in recruiting highly conserved centromeric proteins. Here, we hypothesized that centromeric transcripts may function through a secondary structure rather than sequence conservation. Using mouse embryonic stem cells (ESCs), we show that an imbalance in the levels of forward or reverse minor satellite (MinSat) transcripts leads to severe chromosome segregation defects. We further show that MinSat RNA adopts a stem-loop secondary structure, which is conserved in human α-satellite transcripts. We identify an RNA binding region in CENPC and demonstrate that MinSat transcripts function through the structured region of the RNA. Importantly, mutants that disrupt MinSat secondary structure do not cause segregation defects. We propose that the conserved role of centromeric transcripts relies on their secondary RNA structure.
... Chromosomal rearrangements, fusions and translocations as seen here between chr04 and chr06 and between chr09 and chr010 can occur naturally or otherwise in animals, fungi and plants [146][147][148][149][150]. However, the formation of dicentric chromosomes, for example, are known to be unstable and typically result in the deletion or inactivation of one of centromeres when fixed in a population (indicated by a '?' in Fig. 2c) [ [151,152]]. Large structural genome rearrangements have however been previously observed in the PPEs P. celeri [153] and O. tauri [23], and can be important factors in population adaptation and divergence [154,155] and genome evolution and diversity [147,150]. ...
Genome sequencing and assembly of the photosynthetic picoeukaryotic Picochlorum sp. SENEW3 revealed a compact genome with a reduced gene set, few repetitive sequences, and an organized Rabl-like chromatin structure. Hi-C chromosome conformation capture revealed evidence of possible chromosomal translocations, as well as putative centromere locations. Maintenance of a relatively few selenoproteins, as compared to similarly sized marine picoprasinophytes Mamiellales, and broad halotolerance compared to others in Trebouxiophyceae, suggests evolutionary adaptation to variable salinity environments. Such adaptation may have driven size and genome minimization and have been enabled by the retention of a high number of membrane transporters. Identification of required pathway genes for both CAM and C 4 photosynthetic carbon fixation, known to exist in the marine mamiellale pico-prasinophytes and seaweed Ulva , but few other chlorophyte species, further highlights the unique adaptations of this robust alga. This high-quality assembly provides a significant advance in the resources available for genomic investigations of this and other photosynthetic picoeukaryotes.
... If chromosomes of model organisms were to be compared, most model organisms have monocentric chromosomes [75][76][77]. Each chromosome has only a single centromere that holds the sister chromatids together. ...
... The positioning of the centromere along the chromosome can be varied, but the centromeric DNA and its surroundings are usually condensed into heterochromatin during interphase [78]. The presence of multiple centromeres is typically a result of chromosomal rearrangements and can lead to defects in chromosome segregation [75]. However, the nematode C. elegans has holocentric chromosomes [79]. ...
Chromatin is the complex of DNA and associated proteins found in the nuclei of living organisms. How it is organized is a major research field as it has implications for replication, repair, and gene expression. This review summarizes the current state of the chromatin organization field, with a special focus on chromatin motor complexes cohesin and condensin. Containing the highly conserved SMC proteins, these complexes are responsible for organizing chromatin during cell division. Additionally, research has demonstrated that condensin and cohesin also have important functions during interphase to shape the organization of chromatin and regulate expression of genes. Using the model organism C. elegans, the authors review the current knowledge of how these complexes perform such diverse roles and what open questions still exist in the field.
... The majority of CpG dinucleotides are found in repetitive DNA, known as repetitive elements (REs), which are the most abundant sequence type in the genome [109]. The methylation status of these REs is essential for genome stability, replication, regulation of gene transcription, and nuclear architecture [110][111][112][113]. Demethylation is mediated by the activity of ten-eleven translocation (TET) proteins and thymine-DNA glycosylase (TDG). ...
Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches
... Centromeres are the chromosomal sites where spindle fibers attach via the kinetochore to allow chromosome segregation during cell division. Defects in centromere function can cause chromosome missegregation and aneuploidy, which are linked to cancers, miscarriages, and genetic disorders [1][2][3][4]. Centromeres are characterized by specialized nucleosomes composed of Centromere-Protein A (CENP-A), which replaces canonical histone H3 at centromeric chromatin [5,6]. CENP-A chromatin acts as the foundation for the assembly of kinetochore components. ...
Background
Centromeres are essential for faithful chromosome segregation during mitosis and meiosis. However, the organization of satellite DNA and chromatin at mouse centromeres and pericentromeres is poorly understood due to the challenges of assembling repetitive genomic regions.
Results
Using recently available PacBio long-read sequencing data from the C57BL/6 strain, we find that contrary to the previous reports of their homogeneous nature, both centromeric minor satellites and pericentromeric major satellites exhibit a high degree of variation in sequence and organization within and between arrays. While most arrays are continuous, a significant fraction is interspersed with non-satellite sequences, including transposable elements. Using chromatin immunoprecipitation sequencing (ChIP-seq), we find that the occupancy of CENP-A and H3K9me3 chromatin at centromeric and pericentric regions, respectively, is associated with increased sequence enrichment and homogeneity at these regions. The transposable elements at centromeric regions are not part of functional centromeres as they lack significant CENP-A enrichment. Furthermore, both CENP-A and H3K9me3 nucleosomes occupy minor and major satellites spanning centromeric-pericentric junctions and a low yet significant amount of CENP-A spreads locally at centromere junctions on both pericentric and telocentric sides. Finally, while H3K9me3 nucleosomes display a well-phased organization on major satellite arrays, CENP-A nucleosomes on minor satellite arrays are poorly phased. Interestingly, the homogeneous class of major satellites also phase CENP-A and H3K27me3 nucleosomes, indicating that the nucleosome phasing is an inherent property of homogeneous major satellites.
Conclusions
Our findings reveal that mouse centromeres and pericentromeres display a high diversity in satellite sequence, organization, and chromatin structure.
... Moreover, significant alterations in bulk 5mC modifications of alpha satellites, repeats that are enriched within centromeres, were identified. Methylation changes within repetitive elements carry potential for issues such as inflammation and genomic instability that can result from the formation of dsRNA that activate the innate immune system, as well as DNA damage through retrotransposition-induced double stranded DNA breaks [115][116][117][118]. ...
Aging disrupts cellular processes such as DNA repair and epigenetic control, leading to a gradual buildup of genomic alterations that can have detrimental effects in post-mitotic cells. Genomic alterations in regions of the genome that are rich in repetitive sequences, often termed “dark loci,” are difficult to resolve using traditional sequencing approaches. New long-read technologies offer promising avenues for exploration of previously inaccessible regions of the genome. Using nanopore-based long-read whole-genome sequencing of DNA extracted from aged 18 human brains, we identify previously unreported structural variants and methylation patterns within repetitive DNA, focusing on transposable elements (“jumping genes”) as crucial sources of variation, particularly in dark loci. Our analyses reveal potential somatic insertion variants and provides DNA methylation frequencies for many retrotransposon families. We further demonstrate the utility of this technology for the study of these challenging genomic regions in brains affected by Alzheimer’s disease and identify significant differences in DNA methylation in pathologically normal brains versus those affected by Alzheimer’s disease. Highlighting the power of this approach, we discover specific polymorphic retrotransposons with altered DNA methylation patterns. These retrotransposon loci have the potential to contribute to pathology, warranting further investigation in Alzheimer’s disease research. Taken together, our study provides the first long-read DNA sequencing-based analysis of retrotransposon sequences, structural variants, and DNA methylation in the aging brain affected with Alzheimer’s disease neuropathology.
... Isochromosomes may accelerate tumor growth by altering gene dosage. It is also possible that a centromere becomes unstable in cancer cells [20,21]. This review summarizes the centromere sequence and chromatin in humans and the fission yeast Schizosaccharomyces pombe and discusses recent findings on how centromere integrity is maintained and how GCR occurs at the centromere. ...
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.
... I n mammalian cells, pericentric heterochromatin is essential for higher-order chromosome organization, nuclear architecture, and maintenance of genome integrity 1,2 . Heterochromatin domains exhibit profound conformational changes during cellular senescence with dire consequences for genome integrity, but little is known about the underlying mechanisms 2,3 . ...
The mechanisms leading to changes in mesoscale chromatin organization during cellular aging are unknown. Here, we used transcriptional activator-like effectors, RNA-seq and superresolution analysis to determine the effects of genotoxic stress on oocyte chromatin structure. Major satellites are organized into tightly packed globular structures that coalesce into chromocenters and dynamically associate with the nucleolus. Acute irradiation significantly enhanced chromocenter mobility in transcriptionally inactive oocytes. In transcriptionally active oocytes, irradiation induced a striking unfolding of satellite chromatin fibers and enhanced the expression of transcripts required for protection from oxidative stress (Fermt1, Smg1), recovery from DNA damage (Tlk2, Rad54l) and regulation of heterochromatin assembly (Zfp296, Ski-oncogene). Non-irradiated, senescent oocytes exhibit not only high chromocenter mobility and satellite distension but also a high frequency of extra chromosomal satellite DNA. Notably, analysis of biological aging using an oocyte-specific RNA clock revealed cellular communication, posttranslational protein modifications, chromatin and histone dynamics as the top cellular processes that are dysregulated in both senescent and irradiated oocytes. Our results indicate that unfolding of heterochromatin fibers following acute genotoxic stress or cellular aging induced the formation of distended satellites and that abnormal chromatin structure together with increased chromocenter mobility leads to chromosome instability in senescent oocytes.
... Crossovers between centromeres of non-homologous chromosomes would be expected to produce whole-arm translocations, whereas intrachromosomal crossovers between inverted satellite sequences would produce isochromosomes. Both types of chromosomal aberrations dramatically increase in a sub-set of cancer cell lines ( reviewed in ( 31 ) ) . In oral squamous carcinoma cells, for example, 60% of chromosome aberration breakpoints were located at centromeric regions ( 32 ,33 ) . ...
... Such translocations are fusions of the long arms of two acrocentric chromosomes associated with loss of the short arms. Robertsonian translocation breakpoints are located within the pericentromeres, leading to formation of pseudo-dicentric products, in which only one centromere remains active ( 31 ) . Carriers of Robertsonian translocations are at increased risk of a variety of genetic diseases such as breast cancer, non-Hodgkin lymphoma, and childhood leukemia ( 34 ,35 ) . ...
Although fusions between the centromeres of different human chromosomes have been observed cytologically in cancer cells, since the centromeres are long arrays of satellite sequences, the details of these fusions have been difficult to investigate. We developed methods of detecting recombination within the centromeres of the yeast Saccharomyces cerevisiae (intercentromere recombination). These events occur at similar rates (about 10−8/cell division) between two active or two inactive centromeres. We mapped the breakpoints of most of the recombination events to a region of 43 base pairs of uninterrupted homology between the two centromeres. By whole-genome DNA sequencing, we showed that most (>90%) of the events occur by non-reciprocal recombination (gene conversion/break-induced replication). We also found that intercentromere recombination can involve non-homologous chromosome, generating whole-arm translocations. In addition, intercentromere recombination is associated with very frequent chromosome missegregation. These observations support the conclusion that intercentromere recombination generally has negative genetic consequences.
... Interchromosomal Rearrangements, Telomere Fusion, and Neocentromere Formation Are Not Primary Drivers of Dicentric Chromosomes Following Setd2 Loss. Dicentric chromosomes are a product of chromosome fusion or neocentromere formation and are known to occur in human diseases and promote genomic instability and tumor evolution (9,11,22,23). A common driver of chromosome fusion is telomere dysfunction, and H3K36me3 is present near telomeric or subtelomeric regions (SI Appendix, Fig. S1 B and E) (10). ...
... We isolated metaphase spreads from these cells and observed that, while wild-type SETD2 rescues, R1625C mutated-SETD2 does not, confirming that methyltransferase activity is critical for suppressing dicentric and acentric chromosome formation (SI Appendix, Fig. S4D). While dicentric chromosomes may arise from faulty DSB repair, telomere attrition, or neocentromere formation (22), mechanisms promoting isodicentrics are less well understood. In yeast, mirror-image dicentric and acentric chromosomes can arise through a DNA replication-dependent, DSB-independent manner called faulty template switching or replication template exchange (29,30). ...
Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are likely due to faulty homologous recombination by RAD52. These data provide a mechanism for isochromosome generation and demonstrate that SETD2 and H3K36me3 are essential to prevent the formation of this common mutable chromatin structure known to initiate a cascade of genomic instability in cancer.
