Recombination-mediated genome rearrangements

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Homologous recombination (HR) is a universal DNA double-strand break (DSB) repair pathway that uses an intact DNA molecule as a template. Signature HR reactions are homology search and DNA strand invasion catalyzed by the prototypical RecA-ssDNA filament (Rad51 and Dmc1 in eukaryotes), which produces heteroduplex DNA-containing joint molecules (JMs). These reactions uniquely infringe on the DNA strands association established at replication, on the basis of substantial sequence similarity. For that reason, and despite the high fidelity of its templated nature, DSB repair by HR authorizes the alteration of genome structure, guided by repetitive DNA elements. The resulting structural variations (SVs) can involve vast genomic regions, potentially affecting multiple coding sequences and regulatory elements at once, with possible pathological consequences. Here, we discuss recent advances in our understanding of genetic and molecular vulnerabilities of HR leading to SVs, and of the various fidelity-enforcing factors acting across scales on the balancing act of this complex pathway. An emphasis is put on extra-chomosomal DNAs, both product of, and substrate for HR-mediated chromosomal rearrangements.

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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