At the Beginning of the End and in the Middle of the Beginning: Structure and Maintenance of Telomeric DNA Repeats and Interstitial Telomeric Sequences

Tandem DNA repeats derived from the ancestral (TTAGGG)n run were first detected at chromosome ends of the majority of living organisms, hence the name telomeric DNA repeats. Subsequently, it has become clear that telomeric motifs are also present within chromosomes, and they were suitably called interstitial telomeric sequences (ITSs). It is well known that telomeric DNA repeats play a key role in chromosome stability, preventing end-to-end fusions and precluding the recurrent DNA loss during replication. Recent data suggest that ITSs are also important genomic elements as they confer its karyotype plasticity. In fact, ITSs appeared to be among the most unstable microsatellite sequences as they are highly length polymorphic and can trigger chromosomal fragility and gross chromosomal rearrangements. Importantly, mechanisms responsible for their instability appear to be similar to the mechanisms that maintain the length of genuine telomeres. This review compares the mechanisms of maintenance and dynamic properties of telomeric repeats and ITSs and discusses the implications of these dynamics on genome stability.

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Distribution of Interstitial Telomeric Sequences in Primates and the Pygmy Tree Shrew (Scandentia)

Cytogenetic and Genome Research ◽

10.1159/000467634 ◽

2017 ◽

Vol 151 (3) ◽

pp. 141-150 ◽

Cited By ~ 10

Author(s):

Sofia Mazzoleni ◽

Odessa Schillaci ◽

Luca Sineo ◽

Francesca Dumas

Keyword(s):

Dna Sequences ◽

Tree Shrew ◽

Chromosomal Rearrangements ◽

Primate Species ◽

Telomeric Dna ◽

Erythrocebus Patas ◽

Telomeric Sequences ◽

Interstitial Telomeric Sequences ◽

Cercopithecus Petaurista ◽

Almost All

It has been hypothesized that interstitial telomeric sequences (ITSs), i.e., repeated telomeric DNA sequences found at intrachromosomal sites in many vertebrates, could be correlated to chromosomal rearrangements and plasticity. To test this hypothesis, we hybridized a telomeric PNA probe through FISH on representative species of 2 primate infraorders, Strepsirrhini (Lemur catta, Otolemur garnettii, Nycticebus coucang) and Catarrhini (Erythrocebus patas, Cercopithecus petaurista, Chlorocebus aethiops, Colobus guereza), as well as on 1 species of the order Scandentia, Tupaia minor, used as an outgroup for primates in phylogenetic reconstructions. In almost all primate species analyzed, we found a telomeric pattern only. In Tupaia, the hybridization revealed many bright ITSs on at least 11 chromosome pairs, both biarmed and acrocentric. These ITS signals in Tupaia correspond to fusion points of ancestral human syntenic associations, but are also present in other chromosomes showing synteny to only a single human chromosome. This distribution pattern was compared to that of the heterochromatin regions detected through sequential C-banding performed after FISH. Our results in the analyzed species, compared with literature data on ITSs in primates, allowed us to discuss different mechanisms responsible for the origin and distribution of ITSs, supporting the correlation between rearrangements and ITSs.

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Telomeric DNA sequences in beetle taxa vary with species richness

Scientific Reports ◽

10.1038/s41598-021-92705-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniela Prušáková ◽

Vratislav Peska ◽

Stano Pekár ◽

Michal Bubeník ◽

Lukáš Čížek ◽

...

Keyword(s):

Species Richness ◽

Dna Sequences ◽

Genome Instability ◽

Telomeric Sequence ◽

Dna Repeats ◽

Telomeric Dna ◽

Common Pattern ◽

Telomeric Sequences ◽

Genomic Changes ◽

Protective Structures

AbstractTelomeres are protective structures at the ends of eukaryotic chromosomes, and disruption of their nucleoprotein composition usually results in genome instability and cell death. Telomeric DNA sequences have generally been found to be exceptionally conserved in evolution, and the most common pattern of telomeric sequences across eukaryotes is (TxAyGz)n maintained by telomerase. However, telomerase-added DNA repeats in some insect taxa frequently vary, show unusual features, and can even be absent. It has been speculated about factors that might allow frequent changes in telomere composition in Insecta. Coleoptera (beetles) is the largest of all insect orders and based on previously available data, it seemed that the telomeric sequence of beetles varies to a great extent. We performed an extensive mapping of the (TTAGG)n sequence, the ancestral telomeric sequence in Insects, across the main branches of Coleoptera. Our study indicates that the (TTAGG)n sequence has been repeatedly or completely lost in more than half of the tested beetle superfamilies. Although the exact telomeric motif in most of the (TTAGG)n-negative beetles is unknown, we found that the (TTAGG)n sequence has been replaced by two alternative telomeric motifs, the (TCAGG)n and (TTAGGG)n, in at least three superfamilies of Coleoptera. The diversity of the telomeric motifs was positively related to the species richness of taxa, regardless of the age of the taxa. The presence/absence of the (TTAGG)n sequence highly varied within the Curculionoidea, Chrysomeloidea, and Staphylinoidea, which are the three most diverse superfamilies within Metazoa. Our data supports the hypothesis that telomere dysfunctions can initiate rapid genomic changes that lead to reproductive isolation and speciation.

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The Saccharomyces cerevisiae Rad6 Postreplication Repair and Siz1/Srs2 Homologous Recombination-Inhibiting Pathways Process DNA Damage That Arises in asf1 Mutants

Molecular and Cellular Biology ◽

10.1128/mcb.00894-09 ◽

2009 ◽

Vol 29 (19) ◽

pp. 5226-5237 ◽

Cited By ~ 17

Author(s):

Ellen S. Kats ◽

Jorrit M. Enserink ◽

Sandra Martinez ◽

Richard D. Kolodner

Keyword(s):

Homologous Recombination ◽

Genome Stability ◽

Chromosomal Rearrangements ◽

Nuclear Antigen ◽

Recombination Suppression ◽

Postreplication Repair ◽

Gross Chromosomal Rearrangements ◽

Translesion Bypass ◽

The Relationship ◽

Proliferating Cell

ABSTRACT The Asf1 and Rad6 pathways have been implicated in a number of common processes such as suppression of gross chromosomal rearrangements (GCRs), DNA repair, modification of chromatin, and proper checkpoint functions. We examined the relationship between Asf1 and different gene products implicated in postreplication repair (PRR) pathways in the suppression of GCRs, checkpoint function, sensitivity to hydroxyurea (HU) and methyl methanesulfonate (MMS), and ubiquitination of proliferating cell nuclear antigen (PCNA). We found that defects in Rad6 PRR pathway and Siz1/Srs2 homologous recombination suppression (HRS) pathway genes suppressed the increased GCR rates seen in asf1 mutants, which was independent of translesion bypass polymerases but showed an increased dependency on Dun1. Combining an asf1 deletion with different PRR mutations resulted in a synergistic increase in sensitivity to chronic HU and MMS treatment; however, these double mutants were not checkpoint defective, since they were capable of recovering from acute treatment with HU. Interestingly, we found that Asf1 and Rad6 cooperate in ubiquitination of PCNA, indicating that Rad6 and Asf1 function in parallel pathways that ubiquitinate PCNA. Our results show that ASF1 probably contributes to the maintenance of genome stability through multiple mechanisms, some of which involve the PRR and HRS pathways.

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Extensive Amplification of Telomeric Repeats in the Karyotypically Highly Diverse African Pygmy Mice

Cytogenetic and Genome Research ◽

10.1159/000478297 ◽

2017 ◽

Vol 152 (2) ◽

pp. 55-64 ◽

Cited By ~ 4

Author(s):

Victor Colomina ◽

Josette Catalan ◽

Janice Britton-Davidian ◽

Frédéric Veyrunes

Keyword(s):

Mammalian Species ◽

Chromosomal Rearrangements ◽

Replication Timing ◽

Pericentromeric Region ◽

Chromosomal Evolution ◽

Telomeric Repeats ◽

Telomeric Sequences ◽

Interstitial Telomeric Sequences ◽

Karyotypic Diversity ◽

The One

Telomeres are ribonucleoprotein structures protecting the physical ends of eukaryotic chromosomes. However, telomeric sequences can also occur at non-terminal regions of chromosomes, forming the so-called interstitial telomeric sequences (ITSs). Some ITSs are considered as relics of past chromosomal rearrangements and as such provide important insights into karyotype evolution. By FISH, we explored the distribution of telomeric motifs in the genome of a complex of mammalian species that has long been recognized for its extraordinary karyotypic diversity: the African pygmy mice. This survey involved 5 species, representing 10 highly diverse karyotypes with or without autosomal and sex-autosome robertsonian (Rb) fusions. The study revealed that in species with an ancestral-like karyotype (i.e., no fusions; Mus mattheyi and M. indutus), only terminal telomeres were observed, whereas in species experiencing intense chromosomal evolution (e.g., M. minutoides, M. musculoides), a large amplification of telomeric repeats was also identified in the pericentromeric region of acrocentrics and most metacentrics. We concluded that (i) the mechanism of Rb fusion in the African pygmy mice is different than the one highlighted in the house mouse; (ii) the intensity of the ITS hybridization signal could be a signature of the age of formation of the Rb fusion; (iii) the large amplification of pericentromeric telomeric sequences in acrocentrics may mediate the formation of Rb fusions, and (iv) the ITSs on the sex-autosome fusion Rb(X.1) may participate to the insulation buffer between the sexual and autosomal arms to prevent X inactivation from spreading and silencing autosomal genes and allow the independent regulation of replication timing of both segments.

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Pseudodicentric Chromosome Originating from Autosomes 9 and 21 in a Male Patient with Oligozoospermia

Cytogenetic and Genome Research ◽

10.1159/000504820 ◽

2019 ◽

Vol 159 (4) ◽

pp. 201-207

Author(s):

Marion Beaumont ◽

Elena J. Tucker ◽

Laura Mary ◽

Erika Launay ◽

Yann Lurton ◽

...

Keyword(s):

Male Infertility ◽

Genetic Factors ◽

Chromosomal Rearrangements ◽

Chromosomal Anomalies ◽

Derivative Chromosome ◽

Telomeric Sequences ◽

Dicentric Chromosomes ◽

Interstitial Telomeric Sequences ◽

Cytogenetic Analyses ◽

Reproductive Phenotype

Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient.

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Inverted DNA Repeats Channel Repair of Distant Double-Strand Breaks into Chromatid Fusions and Chromosomal Rearrangements

Molecular and Cellular Biology ◽

10.1128/mcb.01740-06 ◽

2007 ◽

Vol 27 (7) ◽

pp. 2601-2614 ◽

Cited By ~ 70

Author(s):

Kelly VanHulle ◽

Francene J. Lemoine ◽

Vidhya Narayanan ◽

Brandon Downing ◽

Krista Hull ◽

...

Keyword(s):

Chromosomal Rearrangements ◽

Inverted Repeats ◽

Dna Repeats ◽

Dna Breaks ◽

Strand Breaks ◽

Gross Chromosomal Rearrangements ◽

Double Strand Dna Breaks ◽

Single Strand Annealing ◽

Strand Annealing ◽

Break Induced Replication

ABSTRACT Inverted DNA repeats are known to cause genomic instabilities. Here we demonstrate that double-strand DNA breaks (DSBs) introduced a large distance from inverted repeats in the yeast (Saccharomyces cerevisiae) chromosome lead to a burst of genomic instability. Inverted repeats located as far as 21 kb from each other caused chromosome rearrangements in response to a single DSB. We demonstrate that the DSB initiates a pairing interaction between inverted repeats, resulting in the formation of large dicentric inverted dimers. Furthermore, we observed that propagation of cells containing inverted dimers led to gross chromosomal rearrangements, including translocations, truncations, and amplifications. Finally, our data suggest that break-induced replication is responsible for the formation of translocations resulting from anaphase breakage of inverted dimers. We propose a model explaining the formation of inverted dicentric dimers by intermolecular single-strand annealing (SSA) between inverted DNA repeats. According to this model, anaphase breakage of inverted dicentric dimers leads to gross chromosomal rearrangements (GCR). This “SSA-GCR” pathway is likely to be important in the repair of isochromatid breaks resulting from collapsed replication forks, certain types of radiation, or telomere aberrations that mimic isochromatid breaks.

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Understanding the functions of BRCA1 in the DNA-damage response

Biochemical Society Transactions ◽

10.1042/bst0370597 ◽

2009 ◽

Vol 37 (3) ◽

pp. 597-604 ◽

Cited By ~ 26

Author(s):

Maximina H. Yun ◽

Kevin Hiom

Keyword(s):

Dna Damage ◽

Early Onset ◽

Genome Stability ◽

Chromosomal Rearrangements ◽

Dna Lesions ◽

Cell Cycle Checkpoints ◽

Dna Breaks ◽

Gross Chromosomal Rearrangements ◽

Damage Response ◽

Regulation Of Cell Cycle

Inheritance of a mutation in BRCA1 (breast cancer 1 early-onset) results in predisposition to early-onset breast and ovarian cancer. Tumours in these individuals arise after somatic mutation or loss of the wild-type allele. Loss of BRCA1 function leads to a profound increase in genomic instability involving the accumulation of mutations, DNA breaks and gross chromosomal rearrangements. Accordingly, BRCA1 has been implicated as an important factor involved in both the repair of DNA lesions and in the regulation of cell-cycle checkpoints in response to DNA damage. However, the molecular mechanism through which BRCA1 functions to preserve genome stability remains unclear. In the present article, we examine the different ways in which BRCA1 might influence the repair of DNA damage and the preservation of genome integrity, taking into account what is currently known about its interactions with other proteins, its biochemical activity and its nuclear localization.

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Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio

Nucleic Acids Research ◽

10.1093/nar/gkz1006 ◽

2019 ◽

Author(s):

Tobias T Schmidt ◽

Sushma Sharma ◽

Gloria X Reyes ◽

Anna Kolodziejczak ◽

Tina Wagner ◽

...

Keyword(s):

Dna Damage ◽

Genome Stability ◽

Nuclear Dna ◽

Genome Instability ◽

Chromosomal Rearrangements ◽

Dna Integrity ◽

Folylpolyglutamate Synthetase ◽

Cell Extracts ◽

Gross Chromosomal Rearrangements ◽

The Stability

Abstract The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.

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Cdc28/Cdk1 positively and negatively affects genome stability in S. cerevisiae

The Journal of Cell Biology ◽

10.1083/jcb.200811083 ◽

2009 ◽

Vol 185 (3) ◽

pp. 423-437 ◽

Cited By ~ 28

Author(s):

Jorrit M. Enserink ◽

Hans Hombauer ◽

Meng-Er Huang ◽

Richard D. Kolodner

Keyword(s):

Dna Damage ◽

Cell Viability ◽

Genome Stability ◽

Chromosomal Rearrangements ◽

Genetic Network ◽

Telomere Maintenance ◽

Mitotic Catastrophe ◽

Chemical Genetic ◽

Replication Arrest ◽

Gross Chromosomal Rearrangements

We studied the function of the cyclin-dependent kinase Cdc28 (Cdk1) in the DNA damage response and maintenance of genome stability using Saccharomyces cerevisiae. Reduced Cdc28 activity sensitizes cells to chronic DNA damage, but Cdc28 is not required for cell viability upon acute exposure to DNA-damaging agents. Cdc28 is also not required for activation of the DNA damage and replication checkpoints. Chemical–genetic analysis reveals that CDC28 functions in an extensive network of pathways involved in maintenance of genome stability, including homologous recombination, sister chromatid cohesion, the spindle checkpoint, postreplication repair, and telomere maintenance. In addition, Cdc28 and Mre11 appear to cooperate to prevent mitotic catastrophe after DNA replication arrest. We show that reduced Cdc28 activity results in suppression of gross chromosomal rearrangements (GCRs), indicating that Cdc28 is required for formation or recovery of GCRs. Thus, we conclude that Cdc28 functions in a genetic network that supports cell viability during DNA damage while promoting the formation of GCRs.

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SINE-B1 Distribution and Chromosome Rearrangements in the South American Proechimys gr. goeldii (Echimyidae, Rodentia)

Cytogenetic and Genome Research ◽

10.1159/000513106 ◽

2021 ◽

pp. 1-8

Author(s):

Naiara P. Araújo ◽

Radarane S. Sena ◽

Cibele R. Bonvicino ◽

Gustavo C.S. Kuhn ◽

Marta Svartman

Keyword(s):

Transposable Element ◽

Genome Evolution ◽

Significant Role ◽

Sex Chromosomes ◽

Chromosomal Rearrangements ◽

Evolutionary Relationship ◽

Chromosome Rearrangements ◽

South American ◽

Gross Chromosomal Rearrangements

Proechimys species are remarkable for their extensive chromosome rearrangements, representing a good model to understand genome evolution. Herein, we cytogenetically analyzed 3 different cytotypes of Proechimys gr. goeldii to assess their evolutionary relationship. We also mapped the transposable element SINE-B1 on the chromosomes of P. gr. goeldii in order to investigate its distribution among individuals and evaluate its possible contribution to karyotype remodeling in this species. SINE-B1 showed a dispersed distribution along chromosome arms and was also detected at the pericentromeric regions of some chromosomes, including pair 1 and the sex chromosomes, which are involved in chromosome rearrangements. In addition, we describe a new cytotype for P. gr. goeldii, reinforcing the significant role of gross chromosomal rearrangements during the evolution of the genus. The results of FISH with SINE-B1 suggest that this issue should be more deeply investigated for a better understanding of its role in the mechanisms involved in the wide variety of Proechimys karyotypes.

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