Genomic instability

  • Article
    | Open Access

    DNA:RNA hybrids (R-loops) are products of transcription that impact genome integrity and gene expression. Here the authors reveal a mechanism for regulating R-loops in a ubiquitination-dependent manner controlled by the activities of USP11 and KEAP1

    • Mateusz Jurga
    • , Arwa A. Abugable
    •  & Sherif F. El-Khamisy
  • Article
    | Open Access

    Different factors protect cells from harmful R-loops, but the way these are formed is still unclear. Authors show here that R-loops form co-transcriptionally by different manners and cells possess specialized mechanisms to prevent them in each case, a major mechanism being independent of replication and another one being linked to replication.

    • Marta San Martin-Alonso
    • , María E. Soler-Oliva
    •  & Andrés Aguilera
  • Article
    | Open Access

    Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.

    • Yajie Zhao
    • , Stasa Stankovic
    •  & John R. B. Perry
  • Article
    | Open Access

    Telomeres suppress the DNA damage response at chromosome ends. Here the authors show that in budding yeast the activity of the MRX complex in DNA repair and DNA damage signaling is inhibited by telomeric protein Rif2 via a short motif at the N-terminus.

    • Freddy Khayat
    • , Elda Cannavo
    •  & Alessandro Bianchi
  • Article
    | Open Access

    R loops are formed when single-stranded RNA anneals to one strand of DNA, forming three-stranded structures containing DNA-RNA hybrids and the displaced non-template single-stranded DNA. Here the authors reveal that the DNA:RNA helicase UPF1 plays a role in promoting R loops formation at telomeric double strand breaks to stimulate DNA resection and repair.

    • Greg H. P. Ngo
    • , Julia W. Grimstead
    •  & Duncan M. Baird
  • Article
    | Open Access

    BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.

    • Jekaterina Vohhodina
    • , Liana J. Goehring
    •  & David M. Livingston
  • Article
    | Open Access

    XPA-binding protein (XAB)-2 is the human homologue of the yeast pre-mRNA splicing factor Syf1. Here the authors use an in vivo biotinylation tagging approach to show XAB2’s role in DNA repair, RNA splicing and transcription during mammalian development.

    • Evi Goulielmaki
    • , Maria Tsekrekou
    •  & George A. Garinis
  • Article
    | Open Access

    Cornelia de Lange syndrome is a developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The authors, here, by analysing previously identified mutations in BRD4 associated with the disease, reveal that a BRD4 mutation affects DNA damage signalling, and perturbs regulation of DNA repair in mutant cells.

    • Gabrielle Olley
    • , Madapura M. Pradeepa
    •  & Charlene Boumendil
  • Article
    | Open Access

    Lancelet expresses an ancestral RAG transposon, ProtoRAG, which predates human RAGgenes that are responsible for V(D)J recombination and adaptive immunity repertoire generation. Here the authors show that ProtoRAG is functionally regulated by a trans-acting factor, bbYY1, for tuning transposon activity and maintaining genome stability.

    • Song Liu
    • , Shaochun Yuan
    •  & Anlong Xu
  • Article
    | Open Access

    Multiple algorithms exist for predicting heterogeneity and clonal architecture from the bulk sequencing of tumor tissue. Here, the authors report on an algorithm, FastClone, which was developed from a DREAM challenge and show that FastClone can accurately predict clonality in simulated data and data from colon cancer.

    • Yao Xiao
    • , Xueqing Wang
    •  & Yuanfang Guan
  • Article
    | Open Access

    The relationship between DNA damage response (DDR) and regulation of the tolerance to glucose restriction is currently unclear. Here the authors reveal that maintaining a physiological level of histones by Rad53-Spt21 is necessary for glucose tolerance via multiple parallel pathways, including derepression of subtelomeric genes and acetyl-coA regulation by histone acetylation.

    • Christopher Bruhn
    • , Arta Ajazi
    •  & Marco Foiani
  • Article
    | Open Access

    Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.

    • Karin Voordeckers
    • , Camilla Colding
    •  & Kevin J. Verstrepen
  • Article
    | Open Access

    Pop1 and 6 are subunits of RNase P and RNase MRP, which process ribosomal and tRNAs. The authors show that when Pop1 and 6 are impaired, the telomerase subunit Est1 binds telomerase RNA at normal levels, but the binding is unstable. As a result, nuclear import of the telomerase holoenzyme is inhibited.

    • P. Daniela Garcia
    • , Robert W. Leach
    •  & Virginia A. Zakian
  • Article
    | Open Access

    Many industrial organisms are the result of recent or ancient allopolypoidy events. Here the authors iteratively combine the genomes of six yeast species to generate a viable hybrid.

    • David Peris
    • , William G. Alexander
    •  & Chris Todd Hittinger
  • Article
    | Open Access

    Nitrogen-starved fission yeast cells survive for weeks without dividing. Here, the authors show that some of these surviving cells accumulate mutations in the stress- and mitogen-activated protein kinase pathways and outcompete their parental cells, which provide nutrients for the mutant cells.

    • Rostyslav Makarenko
    • , Claire Denis
    •  & Benoît Arcangioli
  • Article
    | Open Access

    The ATM kinase is a key regulator of the DNA damage response to double-strand breaks (DSBs) and its homozygous loss in patients predisposes to lymphoid malignancies. Here, the authors develop a Tdp2−/− Atm−/− double-deficient mouse model to uncover topoisomerase II-induced DSBs as significant drivers of the genomic rearrangements that underpin these tumours.

    • Alejandro Álvarez-Quilón
    • , José Terrón-Bautista
    •  & Felipe Cortés-Ledesma
  • Article
    | Open Access

    Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.

    • Roxanne Oshidari
    • , Richard Huang
    •  & Karim Mekhail
  • Article
    | Open Access

    DNA damage is associated with metabolic disorders, but the mechanism in unclear. Here, the authors show that persistent DNA damage induced by lack of the endonuclease XPF-ERCC1 triggers extracellular vesicle biogenesis in tissue infiltrating macrophages, and that vesicle uptake stimulates glucose uptake in recipient cells, leading to increased inflammation.

    • Evi Goulielmaki
    • , Anna Ioannidou
    •  & George A. Garinis
  • Article
    | Open Access

    Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

    • Rahel T. Florian
    • , Florian Kraft
    •  & Christel Depienne
  • Article
    | Open Access

    During cell division, tetraploidy can drive chromosomal instability (CIN) via supernumerary centrosomes, but it is unclear if this is the only route to CIN. Here the authors show that, in early mouse embryos, tetraploidy can drive chromosomal instability by altering microtubule dynamics and attachment.

    • Lia Mara Gomes Paim
    •  & Greg FitzHarris
  • Article
    | Open Access

    Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.

    • Stefan Gröschel
    • , Daniel Hübschmann
    •  & Stefan Fröhling
  • Article
    | Open Access

    LncRNA TERRA forms RNA-DNA hybrids at telomere sites leading to telomere instability. Here the authors identify the RNA interacting factors NONO and SFPQ as proteins that interact with TERRA and telomere chromatin and reveal putative roles for these factors in telomere integry maintenance by interfering with RNA:DNA hybrid formation.

    • Eleonora Petti
    • , Valentina Buemi
    •  & Stefan Schoeftner
  • Article
    | Open Access

    Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.

    • Xuanxuan Xing
    • , Daniel P. Kane
    •  & Polina V. Shcherbakova
  • Article
    | Open Access

    As cells evolve towards malignancy, somatic mutations arise from defects in DNA damage and repair processes which are each associated with individual mutation signatures. Here the authors show it is possible to recreate cancer mutational signatures in vitro using gene editing experiments in an isogenic human-cell system.

    • Xueqing Zou
    • , Michel Owusu
    •  & Serena Nik-Zainal
  • Article
    | Open Access

    Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

    • Gabriel Balmus
    • , Delphine Larrieu
    •  & Stephen P. Jackson
  • Article
    | Open Access

    Somatic cells can accumulate structural variations such as deletions. Here, Møller et al. show that normal human cells generate large extrachromosomal circular DNAs (eccDNAs), most likely the products of excised DNA, that can be transcriptionally active and, thus, may have phenotypic consequences.

    • Henrik Devitt Møller
    • , Marghoob Mohiyuddin
    •  & Birgitte Regenberg
  • Article
    | Open Access

    Mutations in BRCA1 are associated with an increased risk of breast and ovarian cancer. Here the authors show that EDC4, a component of P-bodies, is a member of the BRCA1 complex with roles in stimulating end resection at breaks.

    • Gonzalo Hernández
    • , María José Ramírez
    •  & Jordi Surrallés
  • Article
    | Open Access

    Break-induced replication (BIR) is a double-strand break repair pathway that can lead to genomic instability. Here the authors show that the absence of Srs2 helicase during BIR leads to uncontrolled binding of Rad51 to single-stranded DNA, which promotes the formation of toxic intermediates that need to be resolved by Mus81 or Yen1.

    • Rajula Elango
    • , Ziwei Sheng
    •  & Anna Malkova
  • Article
    | Open Access

    BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress. Here the authors show that USP21 regulates the ability of tumor cells to repair damaged DNA by regulating BRCA2 stability.

    • Jinping Liu
    • , Alex Kruswick
    •  & Philipp Oberdoerffer