DNA Replication, Damage and Repair in Repeat Instability: Their Role from Bacteria to Genetic Disorders in Humans
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".
Deadline for manuscript submissions: 20 November 2025 | Viewed by 871
Special Issue Editor
Interests: tandem repeats; trinucleotide repeats; microsatellite; minisatellite; repeat expansion; DNA instability; DNA replication; DNA repair; replication slippage
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Special Issue Information
Dear Colleagues,
Repeated DNA sequences in tandem are found across the genomes of many different species, from bacteria to humans. They are frequently highly conserved, as tandem repeats are often found within genes or regulatory regions, suggesting they have an important function. These sequences are prone to high mutation rates, consisting of gain or loss of repeat units, which makes them highly unstable, and, for this reason, the instability of DNA repeats is believed to be a key driver of genome evolution, as they are a source of phenotypic variability. Examples include fast changes in microbial cell surfaces that allow for the evasion of the immune response, variations in internal molecular clocks in flies, and morphological plasticity in mammals. In humans, the instability of trinucleotide repeats leads to large expansions that can interfere with gene expression, protein function, or RNA processing, leading to disease. More than 60 diseases caused by repeat expansions have now been identified, including Huntington's disease, Friedreich’s ataxia, multiple spinocerebellar ataxias, myotonic dystrophy, and Fragile X syndrome.
Repeated DNA sequences can lead to the formation of alternative non-B DNA structures, such as DNA hairpins, cruciform, Z-DNA, H-DNA, and G4 structures, which hinder various cellular processes, such as impairing replication fork progression, favoring transcription–replication collisions in transcribed repeats, and delaying DNA synthesis prior to entry into mitosis, as well as affecting protein binding or direct physical disruption of the DNA helix. Genetic assays and biochemical analyses indicate a relevant role of DNA replication, DNA repair, and transcription machinery in generating instable tandem repeats. Small-scale instability is supposed to occur via the local misalignment of DNA as a consequence of the blockage of DNA replication within a repeated region that is promoted by a defective replication machinery or the formation of DNA secondary structures at the repeat. Large expansions of tandem repeats are not uniquely explained by the DNA slippage model, but more complex mechanisms, including the formation of R-loops. The repair of double-strand breaks by homologous recombination in tandem repeats can result in aberrant repair if the repeat is also present in different chromosomes.
The aim of this Special Issue is to highlight our current understanding of the molecular mechanisms underlying DNA repeat instability, exploring insights gained from in vitro model systems, bacterial and eukaryotic genetic assays, and examining how these mechanisms generate the observed repeat variability.
Prof. Dr. Enrique Viguera
Guest Editor
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Keywords
- DNA repeat instability
- DNA replication
- DNA damage
- DNA repair
- tandem repeats
- trinucleotide repeats
- repeat expansion diseases
- microsatellite instability
- replication slippage
- phenotypic variability
- bacteria
- genetic disorders
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