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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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Stepwise requirements for polymerases δ and θ in theta-mediated end joining
Polymerase delta is required for multiple steps in polymerase theta-dependent repair of chromosome breaks, a pathway targeted in cancer therapy.
- Susanna Stroik
- , Juan Carvajal-Garcia
- & Dale A. Ramsden
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Article
| Open AccessChromatin compartmentalization regulates the response to DNA damage
After the production of double-stranded breaks in mammalian cells, ATM drives the formation of the D compartment, which regulates DNA damage-responsive genes, through the clustering of damaged topologically associating domains, with a mechanism that is consistent with polymer–polymer phase separation.
- Coline Arnould
- , Vincent Rocher
- & Gaëlle Legube
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Article
| Open AccessPolθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis
In mitosis, genome integrity is maintained by DNA polymerase theta-dependent repair of DNA double-strand breaks, which is regulated by Polo-like kinase 1 activity.
- Camille Gelot
- , Marton Tibor Kovacs
- & Raphael Ceccaldi
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Article
| Open AccessLong-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers
Linked-read whole-genome sequencing reveals patterns of structural DNA variants that are specific to homologous recombination deficiency and can be used to distinguish between BRCA1- and BRCA2-deficient phenotypes.
- Jeremy Setton
- , Kevin Hadi
- & Marcin Imieliński
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Structure and function of the RAD51B–RAD51C–RAD51D–XRCC2 tumour suppressor
Structural and biochemical studies of the RAD51B–RAD51C–RAD51D–XRCC2 complex reveal that it uses coupled RAD51B and RAD51C ATPase activities to promote the nucleation and extension of RAD51 nucleoprotein filaments.
- Luke A. Greenhough
- , Chih-Chao Liang
- & Stephen C. West
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Structural insights into BCDX2 complex function in homologous recombination
Analyses of the structure and biochemical properties of the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 reveal details of its role in the repair of DNA double-strand breaks.
- Yashpal Rawal
- , Lijia Jia
- & Shaun K. Olsen
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Break-induced replication orchestrates resection-dependent template switching
Break-induced telomere synthesis initiates recruitment of the SNM1A nuclease, which promotes DNA end resection that in turn allows template switching to enable bypass of lesions.
- Tianpeng Zhang
- , Yashpal Rawal
- & Roger A. Greenberg
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Article
| Open AccessPan-cancer whole-genome comparison of primary and metastatic solid tumours
The genomic differences between primary and metastatic tumours are assessed across 23 cancer types using pan-cancer whole-genome analysis.
- Francisco Martínez-Jiménez
- , Ali Movasati
- & Arne Van Hoeck
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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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Lesion recognition by XPC, TFIIH and XPA in DNA excision repair
Cryo-electron microscopy structures reveal how XPC recognizes DNA lesions and recruits XPA and the TFIIH core complex for lesion verification in nucleotide excision repair.
- Jinseok Kim
- , Chia-Lung Li
- & Wei Yang
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Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats
Epstein–Barr Virus (EBV) nuclear antigen 1 is shown to induce breakage of a fragile site on chromosome 11 by binding to a cluster of EBV-like imperfect palindromic repeats.
- Julia Su Zhou Li
- , Ammal Abbasi
- & Don W. Cleveland
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R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response
RNA–DNA hybrids are immunogenic species that can aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response.
- Magdalena P. Crossley
- , Chenlin Song
- & Karlene A. Cimprich
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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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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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A mechanism for oxidative damage repair at gene regulatory elements
The nuclear mitotic apparatus protein NuMA helps to protect genes from oxidative damage by occupying regions around transcription start sites, binding DNA repair factors and promoting transcription following damage.
- Swagat Ray
- , Arwa A. Abugable
- & Sherif F. El-Khamisy
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Article
| Open AccessMechanism of AAA+ ATPase-mediated RuvAB–Holliday junction branch migration
Structures of the ATP-hydrolysing RuvAB complex captured in multiple conformations provide mechanistic insights into coordinated ATPase and motor activity during DNA recombination.
- Jiri Wald
- , Dirk Fahrenkamp
- & Thomas C. Marlovits
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Breakage of cytoplasmic chromosomes by pathological DNA base excision repair
DNA damage during chromothripsis is caused by deoxyinosine formation on accumulated RNA–DNA hybrids in micronuclei that are then recognized by N-methyl-purine DNA glycosylase and cleaved by apurinic/apyrimidinic endonuclease.
- Shangming Tang
- , Ema Stokasimov
- & David Pellman
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Somatic genomic changes in single Alzheimer’s disease neurons
Analyses of single-cell whole-genome sequencing data show that somatic mutations are increased in the brain of individuals with Alzheimer’s disease compared to neurotypical individuals, with a pattern of genomic damage distinct from that of normal ageing.
- Michael B. Miller
- , August Yue Huang
- & Christopher A. Walsh
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Crucial role and mechanism of transcription-coupled DNA repair in bacteria
Integrated structure–function studies show that transcription-coupled DNA repair (TCR)—rather than global genomic repair—is responsible for most chromosomal repair events in bacteria, and that TCR mainly occurs independently of the Mfd translocase.
- Binod K. Bharati
- , Manjunath Gowder
- & Evgeny Nudler
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| 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
| Open AccessHELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51
HELQ is differentially regulated by RAD51, which stimulates helicase activity, and RPA, which inhibits helicase activity and stimulates annealing.
- Roopesh Anand
- , Erika Buechelmaier
- & Simon J. Boulton
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Activation of homologous recombination in G1 preserves centromeric integrity
Centromeres are able to recruit the homologous recombination machinery during G1 via CENP-A and HJURP, thereby preserving centromeric integrity even in the absence of a sister chromatid.
- Duygu Yilmaz
- , Audrey Furst
- & Evi Soutoglou
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Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response
Endogenous formaldehyde accumulation reveals Cockayne syndrome in mice and stimulates production of the anorexiogenic peptide GDF15 in proximal tubule cells.
- Lee Mulderrig
- , Juan I. Garaycoechea
- & Ketan J. Patel
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FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation
FAM72A differentially controls mutation rates by regulating uracil processing at different stages of the cell cycle, thereby regulating somatic hypermutation and class-switch recombination in B cells.
- Yuqing Feng
- , Conglei Li
- & Alberto Martin
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| Open AccessStructural basis of human transcription–DNA repair coupling
The authors resolve the structure of five complexes containing RNA polymerase II and the CSA and CSB proteins, offering insight into how the repair of DNA lesions is coupled to transcription.
- Goran Kokic
- , Felix R. Wagner
- & Patrick Cramer
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Article
| Open AccessRecA finds homologous DNA by reduced dimensionality search
Observations of rapid repair of double-stranded DNA breaks in sister choromosomes in Escherichia coli are consistent with a reduced-dimensionality-search model of RecA-mediated repair.
- Jakub Wiktor
- , Arvid H. Gynnå
- & Johan Elf
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Molecular basis for DarT ADP-ribosylation of a DNA base
Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria.
- Marion Schuller
- , Rachel E. Butler
- & Ivan Ahel
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BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination
A tandem BRCT-domain-associated ubiquitin-dependent recruitment motif in BARD1 recruits BRCA1 to DNA double-strand breaks (DSBs) to promote homologous recombination and antagonize the 53BP1 DSB repair pathway that mediates non-homologous end joining.
- Jordan R. Becker
- , Gillian Clifford
- & J. Ross Chapman
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Mechanisms of BRCA1–BARD1 nucleosome recognition and ubiquitylation
The authors elucidate the mechanisms for the ubiquitylation specificity and recruitment of the ubiquitin ligase complex BRCA1–BARD1 to damaged DNA within chromatin to facilitate homologous recombination.
- Qi Hu
- , Maria Victoria Botuyan
- & Georges Mer
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Concerted cutting by Spo11 illuminates meiotic DNA break mechanics
A small proportion of Spo11-dependent DNA double-strand breaks are ‘double cuts’—adjacent breaks that occur in concert—revealing that gap repair during meiosis includes that of DNA gaps generated by Spo11 itself.
- Dominic Johnson
- , Margaret Crawford
- & Matthew J. Neale
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RNA transcripts stimulate homologous recombination by forming DR-loops
RNA transcripts stimulate homologous recombination through the formation of DR-loops, intermediate structures that contain both DNA–DNA and DNA–RNA hybrids.
- Jian Ouyang
- , Tribhuwan Yadav
- & Lee Zou
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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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Structural basis of long-range to short-range synaptic transition in NHEJ
Double-strand DNA break repair by the non-homologous end joining pathway involves the transition from a complex that bridges the DNA ends to a complex that aligns the DNA for ligation through the dissociation of the kinase subunits of the DNA-PK complexes.
- Siyu Chen
- , Linda Lee
- & Yuan He
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Neuronal enhancers are hotspots for DNA single-strand break repair
DNA single-strand breaks in neurons accumulate at high levelsin functional enhancers.
- Wei Wu
- , Sarah E. Hill
- & André Nussenzweig
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Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance
Breaks in mitochondrial DNA cause leakage of mitochondrial RNA into the cytoplasm, enhancing immune surveillance and synergizing with nuclear DNA damage to mount a robust type-I interferon immune response.
- Marco Tigano
- , Danielle C. Vargas
- & Agnel Sfeir
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Loop extrusion as a mechanism for formation of DNA damage repair foci
During the repair of double-stranded DNA breaks, cohesin mediates the extrusion of loops of DNA along which phosphorylated H2AX spreads to establish a repair zone.
- Coline Arnould
- , Vincent Rocher
- & Gaëlle Legube
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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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TRF2-mediated telomere protection is dispensable in pluripotent stem cells
Depletion of TRF2—an essential mediator of telomere protection in most mammalian cells—in mouse embryonic stem cells activates a compensatory transcriptional program that renders TRF2 dispensable for their survival and proliferation.
- Marta Markiewicz-Potoczny
- , Anastasia Lobanova
- & Eros Lazzerini Denchi
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Repeat expansions confer WRN dependence in microsatellite-unstable cancers
In cells with microsatellite instability, expanded TA-dinucleotide repeats form cruciform structures that stall replication forks and cause chromosome shattering in the absence of the WRN helicase.
- Niek van Wietmarschen
- , Sriram Sridharan
- & André Nussenzweig
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Bridging of DNA breaks activates PARP2–HPF1 to modify chromatin
The PARP2–HPF1 histone-modifying complex bridges two nucleosomes to align broken DNA ends for ligation, initiating conformational changes that activate PARP2 and enable DNA damage repair.
- Silvija Bilokapic
- , Marcin J. Suskiewicz
- & Mario Halic
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Pervasive lesion segregation shapes cancer genome evolution
Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.
- Sarah J. Aitken
- , Craig J. Anderson
- & Martin S. Taylor
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Multilayered mechanisms ensure that short chromosomes recombine in meiosis
Several mechanisms regulate the distribution of double-strand breaks during meiosis in Saccharomyces cerevisiae, ensuring that the shortest chromosomes are able to successfully recombine.
- Hajime Murakami
- , Isabel Lam
- & Scott Keeney
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DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex
Cryo-EM structures of the FANCI–FANCD2 complex bound to DNA reveal that monoubiquitination triggers structural changes that enable the complex to function as a sliding DNA clamp and coordinate the repair of DNA interstrand crosslinks.
- Renjing Wang
- , Shengliu Wang
- & Nikola P. Pavletich
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Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms
DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism.
- Michael R. Hodskinson
- , Alice Bolner
- & Puck Knipscheer
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DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis
The catalytic subunit of DNA-PK autophosphorylates and contributes to ribosome biogenesis and haematopoiesis by binding to the U3 small nucleolar RNA.
- Zhengping Shao
- , Ryan A. Flynn
- & Eliezer Calo
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Structure of the Fanconi anaemia monoubiquitin ligase complex
The structure of the multiprotein Fanconi anaemia core complex, determined using cryo-electron microscopy and mass spectrometry, shows that the complex adopts an extended asymmetric structure and highlights the structural and functional asymmetry of the RING finger domains.
- Shabih Shakeel
- , Eeson Rajendra
- & Lori A. Passmore
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Stabilization of chromatin topology safeguards genome integrity
Super-resolution microscopy demonstrates how changes in the 3D organization of chromatin protect DNA against excessive degradation following damage.
- Fena Ochs
- , Gopal Karemore
- & Claudia Lukas