title: Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations.
abstract: Gross chromosomal rearrangements (GCRs), such as translocations, deletions or inversions, are often generated by illegitimate repair between two DNA breakages at regions with nucleotide sequences that might potentially adopt a non-B DNA conformation. We previously established a plasmid-based model system that recapitulates palindrome-mediated recurrent chromosomal translocations in humans, and demonstrated that cruciform DNA conformation is required for the translocation-like rearrangements. Here we show that two sequential reactions that cleave the cruciform structures give rise to the translocation: GEN1-mediated resolution that cleaves diagonally at the four-way junction of the cruciform and Artemis-mediated opening of the subsequently formed hairpin ends. Indeed, translocation products in human sperm reveal the remnants of this two-step mechanism. These two intrinsic pathways that normally fulfil vital functions independently, Holliday-junction resolution in homologous recombination and coding joint formation in rearrangement of antigen-receptor genes, act upon the unusual DNA conformation in concert and lead to a subset of recurrent GCRs in humans.
authors.affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Inagaki
authors.forename: Tamae
authors.initials: T
authors.lastname: Ohye
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kogo
authors.forename: Makiko
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: Takema
authors.initials: T
authors.lastname: Kato
authors.forename: Maoqing
authors.initials: M
authors.lastname: Tong
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurahashi
mesh_terms: D020856:AT Rich Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D019457:Chromosome Breakage; D045566:DNA, Cruciform / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement / Q000235:genetics; D057809:HEK293 Cells; D045565:Holliday Junction Resolvases / Q000378:metabolism; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics*; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009711:Nucleotides / Q000235:genetics; D013094:Spermatozoa / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D045566:DNA, Cruciform; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009711:Nucleotides; C426344:DCLRE1C protein, human; D004720:Endonucleases; C533748:GEN1 protein, human; D045565:Holliday Junction Resolvases