Recombination-mediated genome rearrangements
Graphical abstract
Section snippets
The genetic challenge of HR: overlooking the overwhelming
Despite their relatively low abundance in S. cerevisiae, dispersed repeats are expected to be frequently exposed by resection, embedded within the NPF, and used to query the genome [1]. Dispersed DNA repeats greatly outnumber allelic targets, yet the HR machinery manages to quasi-exclusively template repair accurately from the allelic locus (Figure 2a). The stringency of the donor selection process presumably results from two rounds of homology assessments [2], first at the level of dsDNA
DNA joint molecules: structural liabilities for HR fidelity
The second main HR vulnerability lies in the structure of the D-loop, a central JM intermediate of the pathway substrate for three main types of enzymatic activities: structure selective endonucleases (SSEs) that recognize and cleave JM junctions [42]; DNA polymerases that perform displacement DNA synthesis [43]; and DNA helicases/topoisomerases that take hDNA apart (Figure 3a). These activities (or absence thereof) funnel HR into one of its various, more or less conservative subpathways (
The disloyal competition of extrachromosomal DNA repeats
Vast swaths of eukaryotic genomes are made of repeated sequences (e.g. ≃6% in S. cerevisiae; ≃45% in humans), long recognized as a mediator of SVs whose recurrence scales with repeat length [13,56, 57, 58, 59, 60, 61]. DNA repeats can also exist extra-chromosomally, either in the form of retro-transcribed cDNA [62] or as DNA circles [63] (Figure 1). The contribution of these potentially massive sources of repeated template to HR-mediated SV, as well as the delineation of cellular mechanisms and
Where have the repeat-mediated rearrangements been for the last decade?
Analysis of SV junction sequences is the prime basis from which the underlying mutational mechanism is being inferred. Oddly, the predominant role played by non-allelic HR in natural and pathological human variations (e.g. BRCA1 rearrangements, see [74,57]) has been relayed to a second order phenomenon since the replacement of long-range PCR and targeted sequencing by high-throughput short-read sequencing. Increased coverage, longer reads and improved mapping pipelines progressively brings
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We are grateful to Wolf-Dietrich Heyer, Romain Koszul and Hélène Bordelet for their critical reading of the manuscript. We apologize to the many authors whose work could not be cited due to space constraints. Research in the Piazza lab is funded by the CNRS and the European Research Council (ERC) under the European Union’s Horizon 2020 (ERC grant agreement 851006).
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Cancer Epigenetics: An Overview
2022, Archives of Medical ResearchCitation Excerpt :Over the years it has been shown that the abnormal increase in DNA methylation, in the same tumor cells that present hypomethylation occurs in the very localized genomic region; the so-called CpG-islands that frequently coincide with gene promoters; in particular, genes that control the cell cycle, like tumor-suppressor genes (9,10). Therefore, hypomethylation causes de-compaction of large intergenic regions, particularly rich in repetitive sequences and retrotransposon elements causing a general loss of heterochromatin with the subsequent induction of homologous recombination and severe genomic instability associated with cancer (11,12). Conversely, the hypermethylation of CpG-islands causes the so-called CpG-island methylator phenotype, which induces abnormal chromatin compaction and the silencing of gene expression (13).
Recombination of repeat elements generates somatic complexity in human genomes
2022, CellCitation Excerpt :The regions flanking the DSBs are at first converted to single strands by end resection, and the local assembly of the DNA repair complex is then followed by a search for sequences homologous to the exposed strands to be used as a template (Piazza and Heyer, 2019a). If equal loci on sister chromatids or homologous chromosomes are available and are selected as a donor, the resolution of the DNA break can be neutral; conversely, if homologous sequences of non-allelic loci are selected as donors, the repair leads to non-allelic homologous recombination (NAHR) with potentially catastrophic consequences on genome integrity (Chen et al., 2007; Piazza and Heyer, 2019b; Savocco and Piazza, 2021). Alu and L1 elements in particular, together occupying ∼30% of the human genome, have often been found at the breakpoints of NAHR events associated with cancer and other genetic disorders (Beck et al., 2011; Kolomietz et al., 2002; Zhang et al., 2009).
Delineation of two multi-invasion-induced rearrangement pathways that differently affect genome stability
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