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| Open AccessTranslation selectively destroys non-functional transcription complexes
Translation actively dislodges stalled transcription elongation complexes (ECs) from damaged DNA, which enables lesion repair and restoration of transcription activity, and coupled ribosomes discriminate between active ECs and stalled ECs, ensuring destruction of only the latter.
- Jason Woodgate
- , Hamed Mosaei
- & Nikolay Zenkin
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Article |
Transposon-encoded nucleases use guide RNAs to promote their selfish spread
TnpB and IscB nucleases use transposon-encoded guide RNAs to target genomic sequences for cleavage, thereby favouring copying and spreading of transposable elements.
- Chance Meers
- , Hoang C. Le
- & Samuel H. Sternberg
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Article
| Open AccessMitotic clustering of pulverized chromosomes from micronuclei
The CIP2A–TOPBP1 complex tethers fragmented chromosomes from micronuclei for asymmetric mitotic inheritance, explaining distinct patterns of chromosome rearrangements in cancers and genomic disorders.
- Yu-Fen Lin
- , Qing Hu
- & Peter Ly
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Article
| Open AccessA NPAS4–NuA4 complex couples synaptic activity to DNA repair
A neuron-specific activity-dependent DNA repair mechanism is identified, the impairment of which may lead to neurodevelopmental disorders, neurodegeneration and ageing.
- Elizabeth A. Pollina
- , Daniel T. Gilliam
- & Michael E. Greenberg
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Article
| Open AccessInheritance of paternal DNA damage by histone-mediated repair restriction
In Caenorhabditis elegans, paternal exposure to ionizing radiation results in HIS-24 and HPL-1-dependent genome instability phenotypes, causing embryonic lethality in the offspring.
- Siyao Wang
- , David H. Meyer
- & Björn Schumacher
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Article
| Open AccessOvarian cancer mutational processes drive site-specific immune evasion
Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.
- Ignacio Vázquez-García
- , Florian Uhlitz
- & Sohrab P. Shah
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Article |
Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer
Defective DNA interstrand crosslink repair in Fanconi anaemia drives extensive genomic rearrangements, thereby substantially increasing the risk of cancer development.
- Andrew L. H. Webster
- , Mathijs A. Sanders
- & Agata Smogorzewska
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Article
| Open AccessMechanisms of APOBEC3 mutagenesis in human cancer cells
Endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells, and APOBEC3A is the main driver of these mutations.
- Mia Petljak
- , Alexandra Dananberg
- & John Maciejowski
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Article
| Open AccessCCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition
Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.
- David Gallo
- , Jordan T. F. Young
- & Daniel Durocher
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Article
| Open AccessGenetic instability from a single S phase after whole-genome duplication
Extensive DNA damage occurs during the first interphase following induction of tetraploidy in human cells, largely as a result of the lower amount of protein relative to DNA.
- Simon Gemble
- , René Wardenaar
- & Renata Basto
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Article
| Open AccessSignatures of TOP1 transcription-associated mutagenesis in cancer and germline
Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.
- Martin A. M. Reijns
- , David A. Parry
- & Andrew P. Jackson
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Article |
NORAD-induced Pumilio phase separation is required for genome stability
The noncoding RNA NORAD maintains genome stability in mammalian cells by sequestering Pumilio proteins in phase-separated compartments.
- Mahmoud M. Elguindy
- & Joshua T. Mendell
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Review Article |
The central role of DNA damage in the ageing process
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
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Article |
BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2–RAD52
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
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Tracking break-induced replication shows that it stalls at roadblocks
A method of tracking break-induced replication reveals the details of this repair process and shows that it can be impaired by certain genomic elements and by transcription.
- Liping Liu
- , Zhenxin Yan
- & Anna Malkova
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A yeast living ancestor reveals the origin of genomic introgressions
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
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Article |
Regulation of the MLH1–MLH3 endonuclease in meiosis
Reconstitution of the activation of the MLH1–MLH3 endonuclease shows how crossovers are formed during meiosis.
- Elda Cannavo
- , Aurore Sanchez
- & Petr Cejka
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Article |
Chromosomal alterations among age-related haematopoietic clones in Japan
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
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Ensuring meiotic DNA break formation in the mouse pseudoautosomal region
In mice, the pseudoautosomal region of the sex chromosomes undergoes a dynamic structural rearrangement to promote a high rate of DNA double-strand breaks and to ensure X–Y recombination.
- Laurent Acquaviva
- , Michiel Boekhout
- & Scott Keeney
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Article |
Mechanisms and therapeutic implications of hypermutation in gliomas
Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
- Mehdi Touat
- , Yvonne Y. Li
- & Keith L. Ligon
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Article
| Open AccessPatterns of somatic structural variation in human cancer genomes
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
- & Christian von Mering
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Article |
The molecular landscape of ETMR at diagnosis and relapse
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
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Article |
Genetic predisposition to mosaic Y chromosome loss in blood
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
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Letter |
Genome architecture and stability in the Saccharomyces cerevisiae knockout collection
Whole-genome sequencing of the strains of the Saccharomyces cerevisiae gene-knockout collection reveals the effects of the deletion of non-essential genes on genome stability.
- Fabio Puddu
- , Mareike Herzog
- & Stephen P. Jackson
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Letter |
Hypo-osmotic-like stress underlies general cellular defects of aneuploidy
A common aneuploidy gene-expression signature is identified in yeast that is suggestive of hypo-osmotic stress, and which leads to cells that exhibit increased plasma-membrane stress and impaired endocytosis.
- Hung-Ji Tsai
- , Anjali R. Nelliat
- & Rong Li
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Letter |
Female-biased embryonic death from inflammation induced by genomic instability
Genomic instability, caused by MCM mutations, results in embryonic lethality that disproportionally affects female mouse embryos and is rescued by testosterone or ibuprofen treatment, both of which ameliorate inflammatory effects.
- Adrian J. McNairn
- , Chen-Hua Chuang
- & John C. Schimenti
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Letter |
Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks
A deficiency of Dna2 causes duplication of DNA fragments and their insertion into the genome at double-stranded breaks in yeast.
- Yang Yu
- , Nhung Pham
- & Grzegorz Ira
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Article |
Somatic APP gene recombination in Alzheimer’s disease and normal neurons
The gene for the amyloid precursor protein (APP) shows somatic gene recombination in neurons, and the abundance and diversity of APP variants is increased in neurons from individuals with Alzheimer’s disease.
- Ming-Hsiang Lee
- , Benjamin Siddoway
- & Jerold Chun
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Letter |
Gamete fusion triggers bipartite transcription factor assembly to block re-fertilization
During sexual reproduction in Schizosaccharomyces pombe, the rapid reconstitution of a bipartite Mi–Pi transcription complex after fusion blocks re-fertilization and induces meiosis, which ensures that the genome is maintained.
- Aleksandar Vještica
- , Laura Merlini
- & Sophie G. Martin
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Letter |
The shieldin complex mediates 53BP1-dependent DNA repair
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
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Letter |
CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions
Mutations in all three genes encoding ribonuclease H2 sensitize cells to poly(ADP–ribose) polymerase inhibitors by compromising ribonucleotide excision repair.
- Michal Zimmermann
- , Olga Murina
- & Daniel Durocher
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Article |
Nuclear ARP2/3 drives DNA break clustering for homology-directed repair
Polymerization of actin in the cell nucleus, promoted by the ARP2/3 complex, drives the clustering of double-strand DNA breaks into nuclear compartments where they can undergo homology-directed repair.
- Benjamin R. Schrank
- , Tomas Aparicio
- & Jean Gautier
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Article |
Nuclear F-actin and myosins drive relocalization of heterochromatic breaks
Relocalization of heterochromatic double-strand breaks to the nuclear periphery in Drosophila cells occurs via directed motions driven by nuclear actin filaments and myosins activated by the Smc5/6 complex.
- Christopher P. Caridi
- , Carla D’Agostino
- & Irene Chiolo
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Letter |
piRNA-mediated regulation of transposon alternative splicing in the soma and germ line
A new mechanism of pre-mRNA splicing regulation is revealed that is mediated by piRNA pathway components and is dependent on heterochromatin histone modifications.
- Felipe Karam Teixeira
- , Martyna Okuniewska
- & Ruth Lehmann
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Article |
The transcription fidelity factor GreA impedes DNA break repair
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
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Article |
Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism
The mechanism by which formaldehyde, a potent DNA and protein crosslinking agent, is generated from folate is described, with implications for the treatment of certain cancers.
- Guillermo Burgos-Barragan
- , Niek Wit
- & Ketan J. Patel
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Letter |
Rad51-mediated double-strand break repair and mismatch correction of divergent substrates
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
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Letter |
Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice
A restricted diet extends the lives and improves the health of mice with accelerated ageing due to an inability to repair DNA damage.
- W. P. Vermeij
- , M. E. T. Dollé
- & J. H. J. Hoeijmakers
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Letter |
The nature of mutations induced by replication–transcription collisions
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
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Letter |
Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing
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
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Letter |
A mechanism for the suppression of homologous recombination in G1 cells
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
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Letter |
Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes
A high-content phenotypic screening method has been developed allowing the first systematic RNA interference screen for nearly 800 genes mediating mammalian meiosis.
- Sybille Pfender
- , Vitaliy Kuznetsov
- & Melina Schuh
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Article |
Chromothripsis from DNA damage in micronuclei
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
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Letter |
Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells
Transposable elements in mammalian genomes need to be silenced to avoid detrimental genome instability; here, the histone variant H3.3 is shown to have an important role in silencing endogenous retroviral elements.
- Simon J. Elsässer
- , Kyung-Min Noh
- & Laura A. Banaszynski
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Letter |
Transcript-RNA-templated DNA recombination and repair
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
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Article |
Genome-defence small RNAs exapted for epigenetic mating-type inheritance
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
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Article |
Homologue engagement controls meiotic DNA break number and distribution
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
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Letter |
Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration
This paper demonstrates that Pif1 helicase works with polymerase d to promote DNA synthesis through a migrating D-loop, a mechanism used to copy tens of kilobases during repair of chromosome breaks by break-induced replication (BIR).
- Marenda A. Wilson
- , YoungHo Kwon
- & Grzegorz Ira
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Letter |
Migrating bubble during break-induced replication drives conservative DNA synthesis
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