FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Faculty Opinions recommendation of Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726777923.793525028 ◽

2016 ◽

Author(s):

Robert K Herman

Keyword(s):

Caenorhabditis Elegans ◽

H3k9 Methylation ◽

Repeat Instability ◽

Rna:Dna Hybrid

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Faculty Opinions recommendation of Genome-wide detection of tandem DNA repeats that are expanded in autism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738385928.793577268 ◽

2020 ◽

Author(s):

Branko Aleksic

Keyword(s):

Dna Repeats ◽

Genome Wide

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Dynamics of Telomeric DNA Turnover in Yeast

Genetics ◽

10.1093/genetics/160.1.63 ◽

2002 ◽

Vol 160 (1) ◽

pp. 63-73

Author(s):

Michael J McEachern ◽

Dana Hager Underwood ◽

Elizabeth H Blackburn

Keyword(s):

Kluyveromyces Lactis ◽

Mutant Gene ◽

Dna Repeats ◽

Wild Type ◽

Telomeric Dna ◽

Cell Divisions ◽

Dna Turnover ◽

Length Regulation ◽

Turn Over

Abstract Telomerase adds telomeric DNA repeats to telomeric termini using a sequence within its RNA subunit as a template. We characterized two mutations in the Kluyveromyces lactis telomerase RNA gene (TER1) template. Each initially produced normally regulated telomeres. One mutation, ter1-AA, had a cryptic defect in length regulation that was apparent only if the mutant gene was transformed into a TER1 deletion strain to permit extensive replacement of basal wild-type repeats with mutant repeats. This mutant differs from previously studied delayed elongation mutants in a number of properties. The second mutation, TER1-Bcl, which generates a BclI restriction site in newly synthesized telomeric repeats, was indistinguishable from wild type in all phenotypes assayed: cell growth, telomere length, and in vivo telomerase fidelity. TER1-Bcl cells demonstrated that the outer halves of the telomeric repeat tracts turn over within a few hundred cell divisions, while the innermost few repeats typically resisted turnover for at least 3000 cell divisions. Similarly deep but incomplete turnover was also observed in two other TER1 template mutants with highly elongated telomeres. These results indicate that most DNA turnover in functionally normal telomeres is due to gradual replicative sequence loss and additions by telomerase but that there are other processes that also contribute to turnover.

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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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Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders

Genes ◽

10.3390/genes7090070 ◽

2016 ◽

Vol 7 (9) ◽

pp. 70 ◽

Cited By ~ 9

Author(s):

Xiao-Nan Zhao ◽

Karen Usdin

Keyword(s):

Fragile X ◽

Repeat Instability

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Structure of the Chromosome VII Centromere Region in Neurospora crassa: Degenerate Transposons and Simple Repeats

Molecular and Cellular Biology ◽

10.1128/mcb.18.9.5465 ◽

1998 ◽

Vol 18 (9) ◽

pp. 5465-5477 ◽

Cited By ~ 69

Author(s):

Edward B. Cambareri ◽

Rafael Aisner ◽

John Carbon

Keyword(s):

Neurospora Crassa ◽

Yeast Artificial Chromosome ◽

Fragment Length Polymorphism ◽

Artificial Chromosome ◽

Polymorphism Analysis ◽

Dna Repeats ◽

Centromere Region ◽

Simple Repeats ◽

Restriction Fragment Length ◽

Repeat Induced Point Mutation

ABSTRACT DNA from the centromere region of linkage group (LG) VII ofNeurospora crassa was cloned previously from a yeast artificial chromosome library and was found to be atypical ofNeurospora DNA in both composition (AT rich) and complexity (repetitive). We have determined the DNA sequence of a small portion (∼16.1 kb) of this region and have identified a cluster of three new retrotransposon-like elements as well as degenerate fragments from the 3′ end of Tad, a previously identified LINE-like retrotransposon. This region contains a novel full-length but nonmobilecopia-like element, designated Tcen, that is only associated with centromere regions. Adjacent DNA contains portions of a gypsy-like element designated Tgl1. A third new element, Tgl2, shows similarity to theTy3 transposon of Saccharomyces cerevisiae. All three of these elements appear to be degenerate, containing predominantly transition mutations suggestive of the repeat-induced point mutation (RIP) process. Three new simple DNA repeats have also been identified in the LG VII centromere region. While Tcenelements map exclusively to centromere regions by restriction fragment length polymorphism analysis, the defective Tad elements appear to occur most frequently within centromeres but are also found at other loci including telomeres. The characteristics and arrangement of these elements are similar to those seen in theDrosophila centromere, but the relative abundance of each class of repeats, as well as the sequence degeneracy of the transposon-like elements, is unique to Neurospora. These results suggest that the Neurospora centromere is heterochromatic and regional in character, more similar to centromeres of Drosophila than to those of most single-cell yeasts.

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