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| Open AccessStructural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1
Human tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs covalently trapped topoisomerase 1B-DNA complexes and other lesions, and is a target for anticancer drug development. Here the authors use an integrated structural approach to shed light onto the molecular basis of DNA end-processing by Tdp1.
- Fiona J. Flett
- , Emilija Ruksenaite
- & Julia M. Richardson
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Article
| Open AccessSingle-molecule imaging reveals multiple pathways for the recruitment of translesion polymerases after DNA damage
Translesion synthesis (TLS) enables cells to tolerate damaged DNA encountered during replication. Here the authors use super-resolution photoactivation localization microscopy to reveal a lesion type dependent mechanism of recruitment of the TLS polymerase Pol IV following DNA damage.
- Elizabeth S. Thrall
- , James E. Kath
- & Joseph J. Loparo
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Article
| Open AccessDNA damage causes rapid accumulation of phosphoinositides for ATR signaling
Phosphoinositides are enriched in the nucleus and accumulate upon DNA damage but their role in responding to DNA damage is poorly defined. Here, the authors show that phosphoinositides rapidly accumulate at DNA damage sites and are required for ATR recruitment and subsequent Chk1 activation.
- Yu-Hsiu Wang
- , Anushya Hariharan
- & Michael P. Sheetz
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Article
| Open AccessInhibition of NHEJ repair by type II-A CRISPR-Cas systems in bacteria
The double-strand breaks generated by CRISPR-Cas systems are the target of multiple DNA repair pathways. Here the authors find incompatibility between NHEJ and type II-A CRISPR-Cas systems due to Csn2 mediated inhibition of end-joining.
- Aude Bernheim
- , Alicia Calvo-Villamañán
- & David Bikard
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Article
| Open AccessGlobal unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate
Precise orchestration of gene expression regulation upon DNA damage is essential for genome integrity. Here the authors identify a novel widespread stress-triggered defence mechanism that promotes rapid transcription-driven genomic surveillance thus limiting mutagenesis and shaping cancer genomes.
- Matthieu D. Lavigne
- , Dimitris Konstantopoulos
- & Maria Fousteri
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| Open AccessPolη O-GlcNAcylation governs genome integrity during translesion DNA synthesis
Polη is a key player in translesion DNA synthesis. Here, the authors uncover that, in response to DNA damage, Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase to facilitate the timely disassembly of Polη after DNA lesion bypass.
- Xiaolu Ma
- , Hongmei Liu
- & Caixia Guo
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Article
| Open AccessATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice
Cockayne syndrome group B protein (CSB) is a multifunctional chromatin remodeler involved in double-strand break repair. Here the authors investigate the molecular post-translational signals regulating CSB activity.
- Nicole L. Batenburg
- , John R. Walker
- & Xu-Dong Zhu
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Article
| Open AccessBreak-induced replication promotes formation of lethal joint molecules dissolved by Srs2
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
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Article
| Open AccessThe STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery
SUMO and ubiquitin are key signal transducers in several cellular processes including the DNA-damage response. Here the authors describe a method for selective enrichment of ubiquitin substrates for E3 ligases from complex cellular proteomes and identify the SUMO conjugation machinery as direct RNF4 substrates.
- Ramesh Kumar
- , Román González-Prieto
- & Alfred C. O. Vertegaal
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Article
| Open AccessThe HSF1–PARP13–PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis
PARP1 recruitment to DNA lesions is critical for DNA damage repair but how DNA damage induces PARP1 redistribution is largely unknown. Here, the authors provide evidence that PARP1 redistribution and DNA repair in tumor cells depend on the formation of a HSF1–PARP13–PARP1 complex.
- Mitsuaki Fujimoto
- , Ryosuke Takii
- & Akira Nakai
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Article
| Open AccessBRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability
The genomic instability phenotype characteristic of BRCA2-deficient cells is not fully mechanistically understood. Here the authors show BRCA2 inactivation destabilizes RPA-coated single-stranded DNA and leads to toxic non homologous end-joining events.
- Jinhua Han
- , Chunyan Ruan
- & Jun Huang
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Article
| Open AccessASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair
UV-induced mutagenic cyclobutane pyrimidine dimers on nucleosomal DNA are sensed by the damage recognition factors DDB2 and XPC via an unknown mechanism. Here, the authors show that the histone methyltransferase ASH1L regulates the DDB2 to XPC handoff by methylating Lys-4 of histone H3.
- Chiara Balbo Pogliano
- , Marco Gatti
- & Hanspeter Naegeli
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Article
| Open AccessModulation of telomere protection by the PI3K/AKT pathway
Regulation of telomeres and the insulin/PI3K pathway both have roles in aging and cancer development but have not been functionally linked. Here the authors demonstrate that PI3K, via downstream targets, regulates TRF1 via phosphorylation.
- Marinela Méndez-Pertuz
- , Paula Martínez
- & Maria A. Blasco
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Article
| Open AccessDNA Ligase C and Prim-PolC participate in base excision repair in mycobacteria
Ligase D is a conserved DNA repair protein complex that repairs double-strand breaks in stationary phase prokaryotes. Here the authors show that orthologous Ligase C has a role in base excision repair during stationary phase.
- Przemysław Płociński
- , Nigel C. Brissett
- & Aidan J. Doherty
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Article
| Open AccessParallel genome-wide screens identify synthetic viable interactions between the BLM helicase complex and Fanconi anemia
Fanconi anemia is a complex disease affecting multiple DNA repair proteins that resolve DNA crosslinks which can block vital processes. Here the authors use parallel genome-wide screens that identify the BLM helicase complex as a suppressor of Fanconi anemia phenotypes.
- Martin Moder
- , Georgia Velimezi
- & Joanna I. Loizou
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Article
| Open AccessFAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2
FANCD2-associated nuclease 1 (FAN1) is a key protein involved in the metabolism of DNA and in human pathologies. Here, the authors show that FAN1 directly interacts with PCNA at stalled replication forks to control their progression and prevent their collapse.
- Antonio Porro
- , Matteo Berti
- & Josef Jiricny
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Article
| Open AccessAUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway
DNA double strand breaks can be repaired by homology-independent or homology-directed mechanisms. The choice between these pathways is a key event for genomic stability maintenance. Here the authors identify and characterize AUNIP, as a factor involved in tilting the balance towards homology repair.
- Jiangman Lou
- , Hongxia Chen
- & Jun Huang
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Article
| Open AccessReplication fork reversal triggers fork degradation in BRCA2-defective cells
BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.
- Sofija Mijic
- , Ralph Zellweger
- & Massimo Lopes
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Article
| Open AccessID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability
MDC1 is a key component of the DNA damage response and interacts with several factors such as γ-H2AX. Here the authors show that MDC1 interacts with ID3, facilitating MDC1 recruitment to sites of damage and repair of breaks.
- Jung-Hee Lee
- , Seon-Joo Park
- & Ho Jin You
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Article
| Open AccessNon-canonical reader modules of BAZ1A promote recovery from DNA damage
ISWI chromatin remodelers regulate DNA accessibility and have been implicated in DNA damage repair. Here, the authors uncover functions, in response to DNA damage, for the bromodomain of the ISWI subunit BAZ1B and for the non-canonical PHD and bromodomain modules of the paralog BAZ1A.
- Mariano Oppikofer
- , Meredith Sagolla
- & Andrea G. Cochran
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Article
| Open AccessMammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism
APE1 plays an important role in the cellular response to oxidative stress, and mutations are linked to tumor progression and chemoresistance. Here, the authors characterize the interactions of APE1 with RNA and demonstrate a role in microRNA processing.
- Giulia Antoniali
- , Fabrizio Serra
- & Gianluca Tell
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Article
| Open AccessA role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival
Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability.
- Elias Bou Samra
- , Géraldine Buhagiar-Labarchède
- & Mounira Amor-Guéret
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Article
| Open AccessIn trans paired nicking triggers seamless genome editing without double-stranded DNA cutting
CRISPR-Cas9-based gene editing involves double-strand breaks at target sequences, which are often repaired by mutagenic non-homologous end-joining. Here the authors use Cas9 nickases to generate coordinated single-strand breaks in donor and target DNA for precise homology-directed gene editing.
- Xiaoyu Chen
- , Josephine M. Janssen
- & Manuel A. F. V. Gonçalves
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Article
| Open AccessBRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination
BRCA2 mutations promote tumour formation while also paradoxically causing cell lethality. Here the authors generate conditional BRCA2 loss in a non-transformed human mammary cell line and see increased replication stress due to under-replication of DNA.
- Weiran Feng
- & Maria Jasin
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Article
| Open AccessTia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells
Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner.
- Manuel D. Díaz-Muñoz
- , Vladimir Yu. Kiselev
- & Martin Turner
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Article
| Open AccessLinker histone H1 prevents R-loop accumulation and genome instability in heterochromatin
While structural importance of linker histone H1 in packaging eukaryotic genome into chromatin is well known, its biological function remains poorly understood. Here the authors reveal that Drosophila linker histone H1 prevents DNA:RNA hybrids accumulation and genome instability in heterochromatin.
- Aleix Bayona-Feliu
- , Anna Casas-Lamesa
- & Fernando Azorín
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Article
| Open AccessTDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.
- Fernando Gómez-Herreros
- , Guido Zagnoli-Vieira
- & Keith W. Caldecott
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Article
| Open AccessDNA end resection requires constitutive sumoylation of CtIP by CBX4
The choice between non-homologous end-joining and homologous recombination to repair a DNA double-strand break depends on activation of the end resection machinery. Here the authors show that SUMO E3 ligase CBX4 sumoylates subpopulation of CtIP to regulate recruitment to breaks and resection.
- Isabel Soria-Bretones
- , Cristina Cepeda-García
- & Pablo Huertas
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Article
| Open AccessPhosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair
Repair of cyclobutane pyrimidine dimers requires access to DNA by the nucleotide excision repair machinery. Here the authors show that HBO1 facilitates accumulation of SNF2H and ACF1 to make chromatin more accessible after ultraviolet damage.
- Hiroyuki Niida
- , Ryoichi Matsunuma
- & Masatoshi Kitagawa
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Article
| Open AccessDual loss of human POLQ and LIG4 abolishes random integration
Homologous recombination mediated gene targeting is highly inefficient in human cells due to random integration events, Here the authors show that dual repression of polymerase θ and DNA ligase IV eliminate random integration events.
- Shinta Saito
- , Ryo Maeda
- & Noritaka Adachi
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Article
| Open AccessThe anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites
The choice between homologous recombination and non-homologous end-joining is largely influenced by cell cycle. Here the authors show that APCCdh1 promotes homologous recombination by removing USP1, allowing polyubiquitinated histones to recruit BRCA1.
- Kyungsoo Ha
- , Chengxian Ma
- & Pumin Zhang
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Article
| Open AccessIdentification of the elementary structural units of the DNA damage response
Phosphorylated histone H2AX is an early signalling event of DNA double-strand breaks. Here the authors use super-resolution microscopy and ChIP-seq and identify ‘nano-domains’ – chromatin loops decorated by γH2AX and flanked by CTCF.
- Francesco Natale
- , Alexander Rapp
- & M. Cristina Cardoso
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Article
| Open AccessUSP13 regulates the RAP80-BRCA1 complex dependent DNA damage response
RAP80 helps to recruit BRCA1 to double-strand breaks, facilitating DNA damage responses. Here the authors report that phosphorylated USP13 deubiquitinates RAP80 after DNA damage, prompting recruitment to the break site.
- Yunhui Li
- , Kuntian Luo
- & Jian Yuan
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Article
| Open AccessA damaged genome’s transcriptional landscape through multilayered expression profiling around in situ-mapped DNA double-strand breaks
DNA double strand breaks (DSBs) are among the most deleterious types of damage and there is strong evidence indicating a relationship between breaks and transcription. Here the authors provide a high-resolution, genome-wide map of induced DSBs and observe ATM-dependent transcriptional repression.
- Fabio Iannelli
- , Alessandro Galbiati
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessExosomes maintain cellular homeostasis by excreting harmful DNA from cells
The role of exosomes in intercellular communication is well established, however less in known about the biological roles of exosome secretion in exosome-secreting cells. Here the authors show that exosome secretion controls cellular homeostasis in exosome-secreting cells by removing harmful cytoplasmic DNA from cells.
- Akiko Takahashi
- , Ryo Okada
- & Eiji Hara
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Article
| Open AccessBLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks
Double-strand breaks are a major DNA lesion that can occur by endogenous and exogenous processes. Here the authors present BLISS—Breaks LabellingIn Situand Sequencing—to map breaks across the genome.
- Winston X. Yan
- , Reza Mirzazadeh
- & Nicola Crosetto
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Article
| Open AccessA domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease
Human EXOG is crucial for mitochondrial DNA repair. Here the authors present the crystal structures of hEXOG in apo form and as DNA complex and suggest a `tape-measure' activity to generate optimal substrates for mitochondrial base excision repair.
- Michal R. Szymanski
- , Wangsheng Yu
- & Y. Whitney Yin
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Article
| Open AccessPARP3 is a promoter of chromosomal rearrangements and limits G4 DNA
Chromosomal rearrangements are key events in the pathogenesis of a range of disorders. Here the authors utilize a zinc finger nuclease translocation reporter to identify PARP3 as a regulator of these events at sites enriched for G quadruplex DNA.
- Tovah A. Day
- , Jacob V. Layer
- & David M. Weinstock
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Article
| Open AccessDNA single-strand break-induced DNA damage response causes heart failure
DNA damage response (DDR) is activated in cardiomyocytes of the failing heart, but the type of DNA damage leading to DDR is unclear. Higoet al. show that in mice heart failure is caused in part by unrepaired DNA single-strand breaks in cardiomyocytes, which activate persistent DDR and trigger an NF-κB-dependent cardiac inflammation.
- Tomoaki Higo
- , Atsuhiko T. Naito
- & Issei Komuro
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Article
| Open AccessPIF1 family DNA helicases suppress R-loop mediated genome instability at tRNA genes
The budding yeast genome encodes two Pif1 family helicases, Pif1 and Rrm3, previously shown to have distinct functions in the maintenance of telomeres and other aspects of genome stability. Here the authors identify a role for Pif1 (and Rrm3) in promoting DNA replication and suppressing R-loop mediated DNA damage at tRNA genes.
- Phong Lan Thao Tran
- , Thomas J. Pohl
- & Virginia A. Zakian
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Article
| Open AccessDNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
Cell cycle arrest after DNA damage is achieved by the expression of the CDK inhibitor p21. Here the authors show that spontaneous DNA damage incurred in unperturbed cell cycles, leads to cell populations exhibiting a bistable state, with p53 and p21 regulating the proliferation-quiescence decision.
- Alexis R. Barr
- , Samuel Cooper
- & Chris Bakal
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Article
| Open AccessManagement of E. coli sister chromatid cohesion in response to genotoxic stress
Homologous recombination of DNA lesions in bacteria involves sister chromatid pairing. Here, the authors show that RecN promotes contacts between sister chromatids and facilitates repair.
- Elise Vickridge
- , Charlene Planchenault
- & Olivier Espéli
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Article
| Open AccessDNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs
The DNA damage response (DDR) involves site-specific small non-coding RNAs. Here the authors show that telomere dysfunction induces transcription of telomeric DNA damage response RNAs that are necessary for DDR activation, which can be specifically muted by antisense inhibitory oligonucleotides.
- Francesca Rossiello
- , Julio Aguado
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessRad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination
Class switch DNA recombination (CSR) is critical for maturation of antibody response, and relies on Ku-mediated NHEJ of DSBs in the IgH S regions for recombination. This study shows Rad52 contributes to CSR through a Ku-independent alternative NHEJ that introduces microhomologies in S–S junctions.
- Hong Zan
- , Connie Tat
- & Paolo Casali
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Article
| Open AccessA non-canonical mismatch repair pathway in prokaryotes
Despite the importance of mismatch repair for genome stability, many Archaea and almost all Actinobacteria lack MutS and MutL proteins. Here the authors, usingMycobacterium smegmatisas a model, report that NucS/EndoMS endonuclease acts in a distinct mismatch repair pathway.
- A. Castañeda-García
- , A. I. Prieto
- & J. Blázquez
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Article
| Open AccessTelomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids
ICF syndrome cells exhibit shortened telomeres and elevated levels of the noncoding RNA TERRA. Here the authors show this is associated with high levels of DNA damage, suggesting an increase in telomere dysfunction due to the formation of DNA: RNA hybrids
- Shira Sagie
- , Shir Toubiana
- & Sara Selig
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Article
| Open AccessContribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival
We know that defects in DNA repair genes are associated with cancer development. Here the authors eliminate XRCC4, a non-homologous end-joining protein, and p53 in the developing brain and find that this causes glioblastoma development as a consequence of reduced PTEN function.
- Youn-Jung Kang
- , Barbara Balter
- & Catherine T. Yan
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Article
| Open AccessCharacterization of the interplay between DNA repair and CRISPR/Cas9-induced DNA lesions at an endogenous locus
CRISPR-Cas9 has rapidly become a common molecular biology tool for modifying genomes and has been modified to generate single-strand nicks as well as double-strand breaks. Here the authors explore the DNA repair pathways activated by the different variants of Cas9.
- Anne Bothmer
- , Tanushree Phadke
- & Cecilia Cotta-Ramusino
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Article
| Open AccessOxidized nucleotide insertion by pol β confounds ligation during base excision repair
Oxidative stress in cells leads to the oxidations of DNA precursors. Here the authors show that these oxidized precursors can be incorporatedin vivoduring base excision repair, leading to DNA breaks and cytotoxicity.
- Melike Çağlayan
- , Julie K. Horton
- & Samuel H. Wilson