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Multiple Invasions‐Induced Chromosomal Rearrangements
Author(s) -
Piazza Aurele,
Heyer WolfDietrich
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.576.2
Subject(s) - chromosomal translocation , homologous recombination , holliday junction , biology , homology (biology) , cleavage (geology) , genetics , dna , recombination , microbiology and biotechnology , computational biology , gene , paleontology , fracture (geology)
Rare inaccuracies of DNA double‐stranded break repair mechanisms fuel evolution and pathologies by generating structural variants (SV) of the genome. Here we report a new translocation mechanism originating from the homology search process during homologous recombination (HR). The multivalent nature of the Rad51 nucleoprotein filament presumably allows simultaneous sampling of several dsDNA. We characterized “multiple invasions” (MI), a predicted byproduct of this search process in vitro , and developed a genetic assay in yeast cells revealing its capacity to cause translocation of the donors. This HR‐based mechanism does not require homology between the two donors, and inserts the intervening sequence from the invading molecule at the translocation junction. The translocation originates from the unscheduled cleavage of strand exchange intermediates by endonucleases (Mus81, Slx1 and Yen1), while D‐loop disruption activities (Sgs1‐Top3 and Mph1) inhibited translocation. Physical analysis revealed additional SV and aneuploidies in 15–20% of the translocants, indicating that the translocation mechanism can result in a cascade of rearrangements. MI‐induced rearrangements (MIIR) parsimoniously explains human SV junction features and could contribute to the formation of complex chromotriptic rearrangements. Support or Funding Information AP was supported by three postdoctoral fellowships awarded by the ARC, EMBO (ALTF 238‐2013) and the European Union (Marie Curie IOF 628355). This work was supported by the National Institute of Health through grants to WDH.Model of multiple invasions‐induced chromosomal rearrangement