Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

Hidehito Inagaki, Tamae Ohye, Hiroshi Kogo, Makiko Tsutsumi, Takema Kato, Maoqing Tong, Beverly S. Emanuel, Hiroki Kurahashi

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Article number1592
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 10-04-2013

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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