Genomic instability

  • Review Article |

    This Review examines the evidence showing that DNA damage is associated with ageing phenotypes, suggesting that it may have a central role as the cause of ageing.

    • Björn Schumacher
    • , Joris Pothof
    •  & Jan H. J. Hoeijmakers
  • Article |

    Single-stranded, DNA-damage-associated small RNAs generated by a BRCA1–RNA-interference complex promote PALB2–RAD52-mediated DNA repair at transcriptional termination pause sites that contain R-loops and are rich in single-stranded DNA breaks in both quiescent and proliferating cells.

    • Elodie Hatchi
    • , Liana Goehring
    •  & David M. Livingston
  • Article |

    A yeast clonal descendant of an ancient hybridization event is identified and sheds light on the early evolution of the Saccharomyces cerevisiae Alpechin lineage and its abundant Saccharomyces paradoxus introgressions.

    • Melania D’Angiolo
    • , Matteo De Chiara
    •  & Gianni Liti
  • Article |

    Population-specific patterns of genomic mutations and selection of haematopoietic clones in Japanese and European participants predict the divergent rates of chronic lymphocytic leukaemia and T cell leukaemia in these populations.

    • Chikashi Terao
    • , Akari Suzuki
    •  & Yoichiro Kamatani
  • Article
    | Open Access

    Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

    • Yilong Li
    • , Nicola D. Roberts
    •  & Peter J. Campbell
  • Article |

    Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease.

    • Sander Lambo
    • , Susanne N. Gröbner
    •  & Marcel Kool
  • Article |

    A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

    • Deborah J. Thompson
    • , Giulio Genovese
    •  & John R. B. Perry
  • Letter |

    The 53BP1 effector complex shieldin is involved in non-homologous end-joining and immunoglobulin class switching, and acts to protect DNA ends to facilitate the repair of DNA by 53BP1.

    • Sylvie M. Noordermeer
    • , Salomé Adam
    •  & Daniel Durocher
  • Article |

    In Escherichia coli, the control of RNA polymerase backtracking by transcription elongation factors impairs DNA break repair by affecting RecBCD resection and consequently RecA loading at sites far removed from the original DNA break.

    • Priya Sivaramakrishnan
    • , Leonardo A. Sepúlveda
    •  & Christophe Herman
  • Letter |

    DNA repair by break-induced replication begins with the Rad51-mediated invasion of single-stranded DNA into a double-stranded donor template; this study shows that successful recombination between highly mismatched substrates can occur when only five consecutive bases can be paired and that mismatch correction is most efficient near the invading end of the recipient strand.

    • Ranjith Anand
    • , Annette Beach
    •  & James Haber
  • Letter |

    When transcription and replication machineries collide on DNA, they can cause mutations to occur in the area near the collision; these mutations are now shown to include two types—duplications/deletions within the transcription unit and base substitutions in the cis-regulatory element of gene expression.

    • T. Sabari Sankar
    • , Brigitta D. Wastuwidyaningtyas
    •  & Jue D. Wang
  • Letter |

    Maximum-depth sequencing (MDS), a new method of detecting extremely rare variants within a bacterial population, is used to show that mutation rates in Escherichia coli vary across the genome by at least an order of magnitude, and also to uncover mechanisms of antibiotic-induced mutagenesis.

    • Justin Jee
    • , Aviram Rasouly
    •  & Evgeny Nudler
  • Letter |

    A mechanism for the repression of homologous recombination in G1, the stage of the cell cycle preceding replication, is determined; the critical aspects are the interaction between BRCA1 and PALB2–BRCA2, and suppression of DNA-end resection.

    • Alexandre Orthwein
    • , Sylvie M. Noordermeer
    •  & Daniel Durocher
  • Article |

    The mechanism for chromothripsis, “shattered” chromosomes that can be observed in cancer cells, is unknown; here, using live-cell imaging and single-cell sequencing, chromothripsis is shown to occur after a chromosome is isolated into a micronucleus, an abnormal nuclear structure.

    • Cheng-Zhong Zhang
    • , Alexander Spektor
    •  & David Pellman
  • Letter |

    Endogenous RNA transcripts are shown to mediate recombination with yeast chromosomal DNA; as the level of RNAs in the nucleus is quite high, these results may open up new understanding of the plasticity of repair and genome instability mechanisms.

    • Havva Keskin
    • , Ying Shen
    •  & Francesca Storici
  • Article |

    The molecular basis for mating-type determination in the ciliate Paramecium has been elucidated, revealing a novel function for a class of small RNAs — these scnRNAs are typically involved in reprogramming the Paramecium genome during sexual reproduction by recognizing and excising transposable elements, but they are now found to be co-opted to switch off expression of the newly identified mating-type gene mtA by excising its promoter, and to mediate epigenetic inheritance of mating types across sexual generations.

    • Deepankar Pratap Singh
    • , Baptiste Saudemont
    •  & Eric Meyer
  • Article |

    DNA double-stranded breaks (DSBs) are shown to form in greater numbers in yeast cells lacking ZMM proteins, which are traditionally regarded as acting strictly downstream of DSB formation; these findings shed light on how cells balance the beneficial and deleterious outcomes of DSB formation.

    • Drew Thacker
    • , Neeman Mohibullah
    •  & Scott Keeney
  • Letter |

    This paper demonstrates that the mechanism of break-induced replication (BIR) is significantly different from S-phase replication, as it proceeds via a migrating bubble driven by Pif1 helicase, results in conservative inheritance of newly synthesized DNA, and is inherently mutagenic.

    • Natalie Saini
    • , Sreejith Ramakrishnan
    •  & Anna Malkova
  • 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
  • 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