Leaping forks at inverted repeats

Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.
Genes & development (Impact Factor: 10.8). 01/2010; 24(1):5-9. DOI: 10.1101/gad.1884810
Source: PubMed


Genome rearrangements are often associated with genome instability observed in cancer and other pathological disorders. Different types of repeat elements are common in genomes and are prone to instability. S-phase checkpoints, recombination, and telomere maintenance pathways have been implicated in suppressing chromosome rearrangements, but little is known about the molecular mechanisms and the chromosome intermediates generating such genome-wide instability. In the December 15, 2009, issue of Genes & Development, two studies by Paek and colleagues (2861-2875) and Mizuno and colleagues (pp. 2876-2886), demonstrate that nearby inverted repeats in budding and fission yeasts recombine spontaneously and frequently to form dicentric and acentric chromosomes. The recombination mechanism underlying this phenomenon does not appear to require double-strand break formation, and is likely caused by a replication mechanism involving template switching.

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Available from: Dana Branzei, Sep 22, 2014
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    • "The DNA secondary structures are suggested to be involved in regulation at both transcriptional and translational levels; however, when the subtle balance between the replication, transcriptional, and repair machinery is impaired, these secondary structures may induce genetic instability. Alternate structure-forming sequences are known to be unstable and represent hotspots for deletion or recombination in bacteria, yeast, and mammals [17] [18] [19] [20]. "
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    ABSTRACT: In addition to the canonical B-form structure first described by Watson and Crick, DNA can adopt a number of alternative structures. These non-B-form DNA secondary structures form spontaneously on tracts of repeat sequences that are abundant in genomes. In addition, structured forms of DNA with intrastrand pairing may arise on single-stranded DNA produced transiently during various cellular processes. Such secondary structures have a range of biological functions but also induce genetic instability. Increasing evidence suggests that genomic instabilities induced by non-B DNA secondary structures result in predisposition to diseases. Secondary DNA structures also represent a new class of molecular targets for DNA-interactive compounds that might be useful for targeting telomeres and transcriptional control. The equilibrium between the duplex DNA and formation of multistranded non-B-form structures is partly dependent upon the helicases that unwind (resolve) these alternate DNA structures. With special focus on tetraplex, triplex, and cruciform, this paper summarizes the incidence of non-B DNA structures and their association with genomic instability and emphasizes the roles of RecQ-like DNA helicases in genome maintenance by resolution of DNA secondary structures. In future, RecQ helicases are anticipated to be additional molecular targets for cancer chemotherapeutics.
    Full-text · Article · Oct 2011 · Journal of nucleic acids
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    • "The definition of template switching became even more complex due to distinct opinions of whether events classified as such involve a DSB intermediate [33] [34] [35] [36] [37] and if they occur at the stalled fork as means of rescuing the fork or rather behind the replication fork [15,38–41] (Fig. 1). Furthermore, although initially template switching was used to distinguish replication-induced strandannealing events from Rad51-mediated DSB repair and fork rescue, this is not anymore the case. "
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    ABSTRACT: Homologous recombination plays an important role in the maintenance of genome integrity. Arrested forks and DNA lesions trigger strand annealing events, called template switching, which can provide for accurate damage bypass, but can also lead to chromosome rearrangements. Advances have been made in understanding the underlying mechanisms for these events and in elucidating the factors involved. Ubiquitin- and SUMO-mediated modification pathways have emerged as key players in regulating damage-induced template switching. Here I review the biological significance of template switching at the nexus of DNA replication and recombination, and the role of ubiquitin-like modifications in mediating and controlling this process.
    Full-text · Article · Apr 2011 · FEBS letters
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    • "In a reporter gene assay these inverted Alus are 10,000× more unstable in the absence of functional p53 than in the wild type genetic background [84] providing strong support for significant contribution of repetitive elements to genetic instability during tumorigenesis (Fig. 2). In yeast, introduction of a single DSB promotes a boost in genomic instability via recombination events between inverted repetitive elements located as far as 21 kb from one another [86] and other studies show that inverted repeats are unstable even without DSBs [87]. Recombination between inverted Alu repeats frequently does not lead to a clean, homologous recombination event. "
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    ABSTRACT: Genetic instability is one of the principal hallmarks and causative factors in cancer. Human transposable elements (TE) have been reported to cause human diseases, including several types of cancer through insertional mutagenesis of genes critical for preventing or driving malignant transformation. In addition to retrotransposition-associated mutagenesis, TEs have been found to contribute even more genomic rearrangements through non-allelic homologous recombination. TEs also have the potential to generate a wide range of mutations derivation of which is difficult to directly trace to mobile elements, including double strand breaks that may trigger mutagenic genomic rearrangements. Genome-wide hypomethylation of TE promoters and significantly elevated TE expression in almost all human cancers often accompanied by the loss of critical DNA sensing and repair pathways suggests that the negative impact of mobile elements on genome stability should increase as human tumors evolve. The biological consequences of elevated retroelement expression, such as the rate of their amplification, in human cancers remain obscure, particularly, how this increase translates into disease-relevant mutations. This review is focused on the cellular mechanisms that control human TE-associated mutagenesis in cancer and summarizes the current understanding of TE contribution to genetic instability in human malignancies.
    Full-text · Article · Aug 2010 · Seminars in Cancer Biology
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