Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks

Research output: Contribution to journalLetter

Yang Yu, Nhung Pham, Bo Xia, Alma Papusha, Guangyu Wang, Zhenxin Yan, Guang Peng, Kaifu Chen, Grzegorz Ira

Insertions of mobile elements1–4, mitochondrial DNA5 and fragments of nuclear chromosomes6 at DNA double-strand breaks (DSBs) threaten genome integrity and are common in cancer7–9. Insertions of chromosome fragments at V(D)J recombination loci can stimulate antibody diversification10. The origin of insertions of chromosomal fragments and the mechanisms that prevent such insertions remain unknown. Here we reveal a yeast mutant, lacking evolutionarily conserved Dna2 nuclease, that shows frequent insertions of sequences between approximately 0.1 and 1.5 kb in length into DSBs, with many insertions involving multiple joined DNA fragments. Sequencing of around 500 DNA inserts reveals that they originate from Ty retrotransposons (8%), ribosomal DNA (rDNA) (15%) and from throughout the genome, with preference for fragile regions such as origins of replication, R-loops, centromeres, telomeres or replication fork barriers. Inserted fragments are not lost from their original loci and therefore represent duplications. These duplications depend on nonhomologous end-joining (NHEJ) and Pol4. We propose a model in which alternative processing of DNA structures arising in Dna2-deficient cells can result in the release of DNA fragments and their capture at DSBs. Similar DNA insertions at DSBs are expected to occur in any cells with linear extrachromosomal DNA fragments.

Original languageEnglish (US)
Pages (from-to)287-290
Number of pages4
JournalNature
Volume564
Issue number7735
DOIs
StatePublished - Dec 13 2018

PMID: 30518856

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Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. / Yu, Yang; Pham, Nhung; Xia, Bo; Papusha, Alma; Wang, Guangyu; Yan, Zhenxin; Peng, Guang; Chen, Kaifu; Ira, Grzegorz.

In: Nature, Vol. 564, No. 7735, 13.12.2018, p. 287-290.

Research output: Contribution to journalLetter

Harvard

Yu, Y, Pham, N, Xia, B, Papusha, A, Wang, G, Yan, Z, Peng, G, Chen, K & Ira, G 2018, 'Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks' Nature, vol. 564, no. 7735, pp. 287-290. https://doi.org/10.1038/s41586-018-0769-8

APA

Yu, Y., Pham, N., Xia, B., Papusha, A., Wang, G., Yan, Z., ... Ira, G. (2018). Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. Nature, 564(7735), 287-290. https://doi.org/10.1038/s41586-018-0769-8

Vancouver

Yu Y, Pham N, Xia B, Papusha A, Wang G, Yan Z et al. Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. Nature. 2018 Dec 13;564(7735):287-290. https://doi.org/10.1038/s41586-018-0769-8

Author

Yu, Yang ; Pham, Nhung ; Xia, Bo ; Papusha, Alma ; Wang, Guangyu ; Yan, Zhenxin ; Peng, Guang ; Chen, Kaifu ; Ira, Grzegorz. / Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. In: Nature. 2018 ; Vol. 564, No. 7735. pp. 287-290.

BibTeX

@article{8e25660f277141aa9655021c8e48cac0,
title = "Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks",
abstract = "Insertions of mobile elements1–4, mitochondrial DNA5 and fragments of nuclear chromosomes6 at DNA double-strand breaks (DSBs) threaten genome integrity and are common in cancer7–9. Insertions of chromosome fragments at V(D)J recombination loci can stimulate antibody diversification10. The origin of insertions of chromosomal fragments and the mechanisms that prevent such insertions remain unknown. Here we reveal a yeast mutant, lacking evolutionarily conserved Dna2 nuclease, that shows frequent insertions of sequences between approximately 0.1 and 1.5 kb in length into DSBs, with many insertions involving multiple joined DNA fragments. Sequencing of around 500 DNA inserts reveals that they originate from Ty retrotransposons (8{\%}), ribosomal DNA (rDNA) (15{\%}) and from throughout the genome, with preference for fragile regions such as origins of replication, R-loops, centromeres, telomeres or replication fork barriers. Inserted fragments are not lost from their original loci and therefore represent duplications. These duplications depend on nonhomologous end-joining (NHEJ) and Pol4. We propose a model in which alternative processing of DNA structures arising in Dna2-deficient cells can result in the release of DNA fragments and their capture at DSBs. Similar DNA insertions at DSBs are expected to occur in any cells with linear extrachromosomal DNA fragments.",
author = "Yang Yu and Nhung Pham and Bo Xia and Alma Papusha and Guangyu Wang and Zhenxin Yan and Guang Peng and Kaifu Chen and Grzegorz Ira",
year = "2018",
month = "12",
day = "13",
doi = "10.1038/s41586-018-0769-8",
language = "English (US)",
volume = "564",
pages = "287--290",
journal = "Nature",
issn = "0028-0836",
number = "7735",

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RIS

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T1 - Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks

AU - Yu, Yang

AU - Pham, Nhung

AU - Xia, Bo

AU - Papusha, Alma

AU - Wang, Guangyu

AU - Yan, Zhenxin

AU - Peng, Guang

AU - Chen, Kaifu

AU - Ira, Grzegorz

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Insertions of mobile elements1–4, mitochondrial DNA5 and fragments of nuclear chromosomes6 at DNA double-strand breaks (DSBs) threaten genome integrity and are common in cancer7–9. Insertions of chromosome fragments at V(D)J recombination loci can stimulate antibody diversification10. The origin of insertions of chromosomal fragments and the mechanisms that prevent such insertions remain unknown. Here we reveal a yeast mutant, lacking evolutionarily conserved Dna2 nuclease, that shows frequent insertions of sequences between approximately 0.1 and 1.5 kb in length into DSBs, with many insertions involving multiple joined DNA fragments. Sequencing of around 500 DNA inserts reveals that they originate from Ty retrotransposons (8%), ribosomal DNA (rDNA) (15%) and from throughout the genome, with preference for fragile regions such as origins of replication, R-loops, centromeres, telomeres or replication fork barriers. Inserted fragments are not lost from their original loci and therefore represent duplications. These duplications depend on nonhomologous end-joining (NHEJ) and Pol4. We propose a model in which alternative processing of DNA structures arising in Dna2-deficient cells can result in the release of DNA fragments and their capture at DSBs. Similar DNA insertions at DSBs are expected to occur in any cells with linear extrachromosomal DNA fragments.

AB - Insertions of mobile elements1–4, mitochondrial DNA5 and fragments of nuclear chromosomes6 at DNA double-strand breaks (DSBs) threaten genome integrity and are common in cancer7–9. Insertions of chromosome fragments at V(D)J recombination loci can stimulate antibody diversification10. The origin of insertions of chromosomal fragments and the mechanisms that prevent such insertions remain unknown. Here we reveal a yeast mutant, lacking evolutionarily conserved Dna2 nuclease, that shows frequent insertions of sequences between approximately 0.1 and 1.5 kb in length into DSBs, with many insertions involving multiple joined DNA fragments. Sequencing of around 500 DNA inserts reveals that they originate from Ty retrotransposons (8%), ribosomal DNA (rDNA) (15%) and from throughout the genome, with preference for fragile regions such as origins of replication, R-loops, centromeres, telomeres or replication fork barriers. Inserted fragments are not lost from their original loci and therefore represent duplications. These duplications depend on nonhomologous end-joining (NHEJ) and Pol4. We propose a model in which alternative processing of DNA structures arising in Dna2-deficient cells can result in the release of DNA fragments and their capture at DSBs. Similar DNA insertions at DSBs are expected to occur in any cells with linear extrachromosomal DNA fragments.

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