Featured
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Article |
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
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Article |
DNA damage detection in nucleosomes involves DNA register shifting
Cryo-electron microscopy structures reveal that the DNA-repair factor UV-DDB exposes inaccessible nucleosome lesions for binding by inducing a translational shift in the nucleosome position.
- Syota Matsumoto
- , Simone Cavadini
- & Nicolas H. Thomä
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Letter |
TRAIP is a master regulator of DNA interstrand crosslink repair
The E3 ubiquitin ligase TRAIP governs the choice between the NEIL3 or the Fanconi anaemia pathway for the repair of DNA interstrand crosslinks.
- R. Alex Wu
- , Daniel R. Semlow
- & Johannes C. Walter
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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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Letter |
CDK12 regulates DNA repair genes by suppressing intronic polyadenylation
The kinase CDK12 suppresses usage of intronic polyadenylation sites and thereby promotes the expression of genes involved in homologous recombination DNA repair.
- Sara J. Dubbury
- , Paul L. Boutz
- & Phillip A. Sharp
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Article |
DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
DYNLL1 antagonizes end resection of DNA double-strand breaks, thereby inhibiting homologous repair, and the loss of DYNLL1 correlates with poor progression-free survival of patients with BRCA1-mutant ovarian cancer.
- Yizhou Joseph He
- , Khyati Meghani
- & Dipanjan Chowdhury
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Article |
Extensive sex differences at the initiation of genetic recombination
Differential DNA methylation and the long-range effects of chromatin organization lead to pronounced differences in recombination landscape between males and females.
- Kevin Brick
- , Sarah Thibault-Sennett
- & Galina V. Petukhova
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Brief Communications Arising |
Large deletions induced by Cas9 cleavage
- Fatwa Adikusuma
- , Sandra Piltz
- & Paul Q. Thomas
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Letter |
53BP1 cooperation with the REV7–shieldin complex underpins DNA structure-specific NHEJ
The specificity of 53BP1 and its co-factors for particular DNA substrates during non-homologous end joining (NHEJ) derives from REV7–shieldin, a four-subunit DNA-binding complex that is required for REV7-dependent NHEJ but not for REV7-dependent DNA interstrand cross-link repair.
- Hind Ghezraoui
- , Catarina Oliveira
- & J. Ross Chapman
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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 |
53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in
53BP1 and shieldin recruit the CTC1–STN1–TEN1 complex and polymerase-α to sites of DNA damage to help control the repair of double-strand breaks.
- Zachary Mirman
- , Francisca Lottersberger
- & Titia de Lange
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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 |
EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma
The EWS–FLI1 fusion protein, expressed in Ewing sarcoma, increases global transcription, causes accumulation of R loops and replication stress, and impairs BRCA1-mediated repair.
- Aparna Gorthi
- , July Carolina Romero
- & Alexander J. R. Bishop
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Letter |
Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress
Oncogene activation results in firing of ectopic origins of replication within transcribed genes, resulting in replication stress and genome instability.
- Morgane Macheret
- & Thanos D. Halazonetis
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Article |
Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells
Endogenous and alcohol-derived acetaldehyde causes a specific pattern of DNA damage in haemopoietic stem cells; the effects are mitigated by detoxification, specific DNA repair mechanisms and a p53 response.
- Juan I. Garaycoechea
- , Gerry P. Crossan
- & Ketan J. Patel
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Article |
Mechanism of tandem duplication formation in BRCA1-mutant cells
BRCA1, but not BRCA2, suppresses the formation of tandem duplications at stalled replication forks in primary mammalian cells.
- Nicholas A. Willis
- , Richard L. Frock
- & Ralph Scully
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Letter |
Structural basis for the initiation of eukaryotic transcription-coupled DNA repair
Cryo-electron microscopy analysis of yeast Rad26 bound to RNA polymerase II provides insight into the initiation of the transcription-coupled DNA repair mechanism in eukaryotes.
- Jun Xu
- , Indrajit Lahiri
- & Dong Wang
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Letter |
A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair
A signalling mechanism in human cells for sensing DNA damage induced by alkylation involves ubiquitin-dependent recruitment of the alkylation repair complex ASCC to the vicinity of the damage and co-localization with transcription and splicing factors.
- Joshua R. Brickner
- , Jennifer M. Soll
- & Nima Mosammaparast
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Article |
BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing
The tumour suppressor complex BRCA1–BARD1, which facilitates the generation of a single-stranded DNA template during homologous recombination, also binds to the recombinase RAD51 and enhances its function.
- Weixing Zhao
- , Justin B. Steinfeld
- & Patrick Sung
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Letter |
Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN
CYREN is a direct inhibitor of classical non-homologous end joining that promotes error-free repair by homologous recombination during the S and G2 phases of the cell cycle.
- Nausica Arnoult
- , Adriana Correia
- & Jan Karlseder
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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 |
cGAS surveillance of micronuclei links genome instability to innate immunity
The cytoplasmic DNA sensor cGAS detects DNA in ruptured micronuclei and activates an innate immune response.
- Karen J. Mackenzie
- , Paula Carroll
- & Andrew P. Jackson
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Letter |
Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage
The structure of Cpf1, a CRISPR–Cas/RNA-guided nuclease, is presented with a three-stranded RNA–DNA loop after cleavage, providing insight into its working mechanism.
- Stefano Stella
- , Pablo Alcón
- & Guillermo Montoya
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Letter |
RNA m6A methylation regulates the ultraviolet-induced DNA damage response
Methylation at the 6 position of adenosine (m6A) in RNA is rapidly and transiently induced at DNA damage sites in response to ultraviolet irradiation.
- Yang Xiang
- , Benoit Laurent
- & Yang Shi
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Article |
TIRR regulates 53BP1 by masking its histone methyl-lysine binding function
A new protein, Tudor interacting repair regulator (TIRR), affects DNA repair by masking the chromatin interaction domain of 53BP1, thereby preventing its recruitment to double-strand breaks.
- Pascal Drané
- , Marie-Eve Brault
- & Dipanjan Chowdhury
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Letter |
Cascading MutS and MutL sliding clamps control DNA diffusion to activate mismatch repair
MutS and MutL—the highly conserved core proteins responsible for the repair of mismatched DNA—form sequential stable sliding clamps that together modulate one-dimensional diffusion along the DNA and, with MutH, facilitate the search for a distant excision initiation site.
- Jiaquan Liu
- , Jeungphill Hanne
- & Richard Fishel
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Article |
Break-induced telomere synthesis underlies alternative telomere maintenance
Alternative lengthening of telomeres in cancer cells is initiated by a specialized replisome and noncanonical homologous recombination at damaged telomeres, culminating in the synthesis of long tracts of telomere DNA.
- Robert L. Dilley
- , Priyanka Verma
- & Roger A. Greenberg
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Article |
Capturing a substrate in an activated RING E3/E2–SUMO complex
A new method based on protein engineering to trap an intact complex between Siz1, SUMO-bound E2, and PCNA for structure determination.
- Frederick C. Streich Jr
- & Christopher D. Lima
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Letter |
Reconstruction of bacterial transcription-coupled repair at single-molecule resolution
Single-molecule assays show that the recruitment of UvrA and UvrAB to Mfd–RNA polymerase complex formed on a DNA lesion arrests the translocating complex and causes its dissolution.
- Jun Fan
- , Mathieu Leroux-Coyau
- & Terence R. Strick
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Letter |
The structural basis of modified nucleosome recognition by 53BP1
A cryo-electron microscopy structure of the DNA damage repair protein 53BP1 bound to a nucleosome illuminates the way 53BP1 recognizes two types of histone modifications (a methyl group and a ubiquitin moiety), and provides insight into the highly specified recognition and recruitment of 53BP1 to modified chromatin.
- Marcus D. Wilson
- , Samir Benlekbir
- & Daniel Durocher
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Letter |
Sliding sleeves of XRCC4–XLF bridge DNA and connect fragments of broken DNA
A combination of single-molecule techniques shows that the repair proteins XRCC4 and XLF form heteromeric mobile sleeve-like complexes that can bridge and hold together fragments of broken DNA.
- Ineke Brouwer
- , Gerrit Sitters
- & Gijs J. L. Wuite
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Article |
Replication fork stability confers chemoresistance in BRCA-deficient cells
Protection of nascent DNA from degradation provides a mechanism that can promote synthetic viability and drug resistance in Brca-deficient cells without restoring homologous recombination at double-strand breaks.
- Arnab Ray Chaudhuri
- , Elsa Callen
- & André Nussenzweig
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Letter |
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
CRISPR/Cas9 DNA editing creates a double-stranded break in the target DNA, which can frequently generate random insertion or deletion of bases (indels); a new genome editing approach combining Cas9 with a cytidine deaminase is described here, which corrects point mutations more efficiently than canonical Cas9, while avoiding double-stranded breaks and indel formation.
- Alexis C. Komor
- , Yongjoo B. Kim
- & David R. Liu
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Letter |
Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes
Analysis of 1,161 cancer genomes across 14 cancer types shows that increased mutation density at gene promoters can be linked to transcription initiation activity and impairment of nucleotide excision repair.
- Dilmi Perera
- , Rebecca C. Poulos
- & Jason W. H. Wong
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Letter |
Nucleotide excision repair is impaired by binding of transcription factors to DNA
An analysis of cancer genomic data reveals an increased rate of somatic mutations at active transcription factor binding sites located both within promoter regions and distal from genes; the increased mutation rate at these genomic regions can be explained by reduced accessibility of the protein-bound DNA to nucleotide excision repair machinery.
- Radhakrishnan Sabarinathan
- , Loris Mularoni
- & Núria López-Bigas
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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 |
The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions
Crystal structures of the DNA glycosylase AlkD with DNA containing various modified bases show that neither substrate recognition nor catalysis use a base-flipping mechanism; instead, AlkD scans the phosphodeoxyribose backbone for increased cationic charge imparted by the alkylated base, and then uses the positive charge to facilitate cleavage of the glycosidic bond, thus explaining the specificity of AlkD for cationic lesions.
- Elwood A. Mullins
- , Rongxin Shi
- & Brandt F. Eichman
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Letter |
Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage
At the initiation of DNA double-strand break repair, a number of ubiquitylation events occur; here, the RNF8 ubiquitin E3 ligase and the ubiquitin-conjugating E2 enzyme, UBC13, are shown to primarily modify H1-type linker histones, via a K63 linkage.
- Tina Thorslund
- , Anita Ripplinger
- & Niels Mailand
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Letter |
Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching
High-throughput genome-wide sequencing reveals why class switch recombination in the IgH locus, an essential step in the process of antibody generation, has a directional joining bias towards deletion rather than inversion.
- Junchao Dong
- , Rohit A. Panchakshari
- & Frederick W. Alt
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Article |
The core spliceosome as target and effector of non-canonical ATM signalling
Transcription-blocking DNA lesions result in chromatin displacement of core spliceosomes containing U2 and U5 snRNPs; consequently, R-loops containing the nascent transcript are formed, which activate ATM in a feed-forward fashion to influence spliceosome dynamics and alternative splicing.
- Maria Tresini
- , Daniël O. Warmerdam
- & Jurgen A. Marteijn
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Letter |
REV7 counteracts DNA double-strand break resection and affects PARP inhibition
Loss of REV7 is shown to regulate end resection of double-stranded DNA breaks in BRCA1-deficient cells, leading to PARP inhibitor resistance and restoration of homologous recombination; REV7 dictates pathway choice in BRCA1-deficient cells and during immunoglobulin class switching.
- Guotai Xu
- , J. Ross Chapman
- & Sven Rottenberg
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Letter |
MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection
MAD2L2 regulates DNA repair at deprotected telomeres and at ionizing-radiation-induced double-stranded DNA breaks by inhibiting resection of the 5′ ends; the ends are thus shunted into the non-homologous end-joining pathway.
- Vera Boersma
- , Nathalie Moatti
- & Jacqueline J. L. Jacobs
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Letter |
Differential DNA mismatch repair underlies mutation rate variation across the human genome
An analysis of how regional mutation rates vary across 652 tumours identifies variable DNA mismatch repair as the basis of the characteristic regional variation in mutation rates seen across the human genome; the results show that differential DNA repair, rather than differential mutation supply, is likely to be the primary cause of this variation.
- Fran Supek
- & Ben Lehner
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Letter |
Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination
Next-generation sequencing technology is used to show that the error-prone polymerase θ (Polθ) is needed to promote alternative non-homologous end joining at telomeres, and during chromosomal translocations, while counteracting homologous recombination; inhibition of Polθ represents a potential therapeutic strategy for tumours that have mutations in homology-directed repair genes.
- Pedro A. Mateos-Gomez
- , Fade Gong
- & Agnel Sfeir
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Letter |
Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair
In studies in mammalian cells, polymerase theta (Polθ, also known as POLQ) is identified as the polymerase responsible for non-homologous end joining DNA repair; this DNA repair pathway acts in many tumours when homologous recombination is inactivated and the identification of the polymerase responsible may aid the development of new therapeutic approaches.
- Raphael Ceccaldi
- , Jessica C. Liu
- & Alan D. D’Andrea
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Letter |
Tel1ATM-mediated interference suppresses clustered meiotic double-strand-break formation
Meiotic recombination is initiated by a fairly uniform distribution of hundreds of DNA double-strand breaks catalysed by the Spo11 protein; here, Tel1 (orthologue of human ATM) is shown to be required for the localized inhibition that prevents double-strand breaks from forming close to one another.
- Valerie Garcia
- , Stephen Gray
- & Matthew J. Neale
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Letter |
Sae2 promotes dsDNA endonuclease activity within Mre11–Rad50–Xrs2 to resect DNA breaks
The MRX complex, required for double-strand break (DSB) repair by homologous recombination, has 3′ to 5′ exonuclease activity, but homologous recombination at a DSB uses a 3′-tailed molecule, which requires resection of the 5′ strand; here it is shown that in yeast, Sae2 nuclease promotes MRX to make an initial endonucleolytic cut on the 5′ strand that may allow MRX to digest the 5′ strand back to the end in a 3′ to 5′ fashion.
- Elda Cannavo
- & Petr Cejka