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 language | English |
|---|---|
| Article number | 1592 |
| Journal | Nature Communications |
| Volume | 4 |
| DOIs | |
| Publication status | Published - 10-04-2013 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations. / Inagaki, Hidehito; Ohye, Tamae; Kogo, Hiroshi; Tsutsumi, Makiko; Kato, Takema; Tong, Maoqing; Emanuel, Beverly S.; Kurahashi, Hiroki.
In: Nature Communications, Vol. 4, 1592, 10.04.2013.Research output: Contribution to journal › Article
TY - JOUR
T1 - Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations
AU - Inagaki, Hidehito
AU - Ohye, Tamae
AU - Kogo, Hiroshi
AU - Tsutsumi, Makiko
AU - Kato, Takema
AU - Tong, Maoqing
AU - Emanuel, Beverly S.
AU - Kurahashi, Hiroki
PY - 2013/4/10
Y1 - 2013/4/10
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms2595
DO - 10.1038/ncomms2595
M3 - Article
C2 - 23481400
AN - SCOPUS:84875847199
VL - 4
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1592
ER -