Genomic instability articles within Nature

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  • Letter |

    Stalling of replication forks in sequences that have non-allelic repeats can lead to genomic rearrangements; here two pathways consistent with homologous recombination and error-free post-replication repair fuse identical and mismatched repeats, respectively, thus inducing chromosomal rearrangements in mouse embryonic stem cells.

    • Lingchuan Hu
    • , Tae Moon Kim
    •  & Paul Hasty

  • Letter |

    The site of collision between two chromosome replication forks can be used to reinitiate replication independent of an active origin, with potentially pathogenic effects.

    • Christian J. Rudolph
    • , Amy L. Upton
    •  & Robert G. Lloyd

  • Letter |

    Misrepair of DNA double strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin and T-cell receptor loci has been implicated in the pathogenesis of lymphoid malignancies. Here, the RAG2 carboxy terminus is shown to be critical for maintaining genomic stability. Rag2c/c p53−/− mice, unlike Rag1c/c p53−/− and p53−/− mice, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. These results reveal a new 'genome guardian' role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2c/c p53−/− and Atm−/− mice.

    • Ludovic Deriano
    • , Julie Chaumeil
    •  & David B. Roth

  • Letter |

    Studies have indicated an undefined role in DNA replication for CENP-B, a DNA binding protein associated with heterochromatin, centromeres and retrotransposon long terminal repeats (LTRs). Here it is shown that Sap1, which binds LTRs, promotes genomic instability when CENP-B activity is absent. CENP-B facilitates replication fork progression through LTRs in a way that protects against rearrangements.

    • Mikel Zaratiegui
    • , Matthew W. Vaughn
    •  & Robert A. Martienssen

  • News & Views |

    Prognosis for patients with pancreatic cancer is bleak, often owing to late diagnosis. The estimate that at least 15 years pass from tumour initiation to malignancy offers hope for early detection and prevention. See Letters p.1109 & p.1114

    • E. Georg Luebeck

  • Letter |

    Pancreatic cancer is highly aggressive, usually because of widespread metastasis. Here, next-generation DNA sequencing has been used to detect genomic rearrangements in 13 patients with pancreatic cancer and to explore clonal relationships among metastases. The results reveal not only considerable inter-patient heterogeneity, but also ongoing genomic instability and evolution during the development of metastases.

    • Peter J. Campbell
    • , Shinichi Yachida
    •  & P. Andrew Futreal

  • Article |

    Zscan4 is shown to be involved in maintaining telomeres in embryonic stem (ES) cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once within nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis–specific homologous recombination genes. Knocking down Zscan4 shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by eight passages.

    • Michal Zalzman
    • , Geppino Falco
    •  & Minoru S. H. Ko

  • Letter |

    Genomic instability has been implicated in tumour development. Here, a new mouse model of Kras-driven lung tumours has been developed, in which genomic instability is caused by overexpression of the mitotic checkpoint protein Mad2. In this model, inhibiting Kras leads to tumour regression, as shown previously. But tumours recur at a much higher rate.

    • Rocio Sotillo
    • , Juan-Manuel Schvartzman
    •  & Robert Benezra

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