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| Open AccessCrosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin
DNA end resection initiating DNA repair by homologous recombination needs to be delicately regulated. This study shows the interplay between SUMOylation and ubiquitylation maintains MRE11 homeostasis on chromatin, thus facilitating genome stability.
- Tao Zhang
- , Han Yang
- & Weibin Wang
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Article
| Open AccessThe KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1
Protection of replication forks against nucleolytic degradation is crucial for genome stability. Here, Dhoonmoon et al identify PARP14 and the KU complex as essential regulators of fork degradation by MRE11 and EXO1 nucleases in BRCA-deficient cells.
- Ashna Dhoonmoon
- , Claudia M. Nicolae
- & George-Lucian Moldovan
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Article
| Open AccessEfficient DNA fluorescence labeling via base excision trapping
Methods for fluorescently labelling DNAs are expensive and labour-intensive. Here the authors report an in situ DNA labelling strategy for oligonucleotides as well as dsDNA that makes use of aldehyde-reactive rotor dyes to trap AP sites resulting from excision of deaminated DNA bases.
- Yong Woong Jun
- , Emily M. Harcourt
- & Eric T. Kool
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Article
| Open AccessXPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair
Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.
- Charlotte Blessing
- , Katja Apelt
- & Martijn S. Luijsterburg
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Article
| Open AccessUltra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.
- M. Kyle Cromer
- , Valentin V. Barsan
- & Matthew H. Porteus
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Article
| Open AccessRecursive Editing improves homology-directed repair through retargeting of undesired outcomes
CRISPR-Cas induced HDR methods tend to have a low efficiency. Here the authors report an HDR improvement strategy, Recursive Editing, that selectively retargets undesired indel outcomes to create additional opportunities for HDR; they introduce REtarget, a tool for Recursive Editing experimental design.
- Lukas Möller
- , Eric J. Aird
- & Jacob E. Corn
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Article
| Open AccessTP53-dependent toxicity of CRISPR/Cas9 cuts is differential across genomic loci and can confound genetic screening
Toxicity of CRISPR/Cas9 induced DNA breaks depends on their repair mechanism, and on the chromatin environment at the cut site. Here the authors show that edits in active genes or regulatory elements can incur a higher toxicity via a TP53-dependent mechanism.
- Miguel M. Álvarez
- , Josep Biayna
- & Fran Supek
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Article
| Open AccessPoly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection
Poly(ADP) ribose polymerase (PARP) activity promotes, but is not required for, chromosome break repair by polymerase theta-mediated end joining (TMEJ). PARP activity promotes TMEJ by stimulating resection, a process that controls pathway choice.
- Megan E. Luedeman
- , Susanna Stroik
- & Dale A. Ramsden
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Article
| Open AccessDistinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis
This manuscript elucidates new mechanisms of mutagenesis in mycobacteria by implicating two translesion DNA polymerases in genome diversification, including creating the mutations that underlie all antibiotic resistance in these global pathogens.
- Pierre Dupuy
- , Shreya Ghosh
- & Michael S. Glickman
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Article
| Open AccessROR2 regulates self-renewal and maintenance of hair follicle stem cells
Wnt signaling functions in tissue homeostasis and tumorigenesis. Here the authors show that ROR2, a Wnt receptor, plays roles not only in transducing Wnt signaling, but also in regulation of DNA damage response critical for stem cell maintenance.
- Anthony Veltri
- , Christopher M. R. Lang
- & Wen-Hui Lien
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Article
| Open AccessTDP1-independent pathways in the process and repair of TOP1-induced DNA damage
Here the authors find that MUS81 mediates excess DNA double strand break (DSB) generation in TDP1 KO cells after camptothecin treatment. They show that TOP1 cleavage complexes can be either resolved directly by TDP1 or be converted into DSBs and repaired further by the Homologous Recombination pathway.
- Huimin Zhang
- , Yun Xiong
- & Junjie Chen
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Article
| Open AccessThe CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis
In this work, CIP2A is discovered as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability.
- Mara De Marco Zompit
- , Mònica Torres Esteban
- & Manuel Stucki
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Article
| Open AccessWASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage
Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage.
- Seong-Su Han
- , Kuo-Kuang Wen
- & Yatin M. Vyas
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Article
| Open AccessSHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination
SHLD1, as a component of the Shieldin (SHLD) complex, mediates DNA repair via non-homologous end-joining (NHEJ), an essential process during lymphocyte development. Here the authors show that SHLD1 is actually dispensable for lymphocyte development and V(D)J recombination, but is essential for class-switching recombination in activated B cells.
- Estelle Vincendeau
- , Wenming Wei
- & Ludovic Deriano
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Article
| Open AccessThe importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened
DNAPKcs and its kinase activity are required for blunt DNA break end joining when the bridging factor XLF is weakened, but for homologous recombination and radiation resistance, the influence of DNAPKcs is not further enhanced with loss of XLF.
- Metztli Cisneros-Aguirre
- , Felicia Wednesday Lopezcolorado
- & Jeremy M. Stark
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Article
| Open AccessDNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II
DNA damage inhibits elongating RNA polymerase II, but also initiates genome-wide transcriptional responses. Here the authors reveal that particularly promoter-bound Pol II is degraded upon DNA damage in a GSK3 signaling-mediated response.
- Barbara Steurer
- , Roel C. Janssens
- & Jurgen Marteijn
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Article
| Open AccessCoiled-coil heterodimer-based recruitment of an exonuclease to CRISPR/Cas for enhanced gene editing
The CRISPR/Cas system has emerged as a powerful and versatile genome engineering tool. Here the authors couple Cas9 to effector protein Exonuclease III via coiled-coil mediated interactions, termed CCExo, leading to increased deletion sizes and enhanced gene knock-out efficiencies in cell lines, primary cells and in vivo.
- Duško Lainšček
- , Vida Forstnerič
- & Roman Jerala
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Article
| Open AccessCas9-induced large deletions and small indels are controlled in a convergent fashion
CRISPR/Cas9 system has revolutionized science and therapy, but DNA damage it causes often goes beyond the desired ’precision editing’. Here, the authors identify general and target specific DNA repair pathways responsible for unwanted mutagenesis.
- Michael Kosicki
- , Felicity Allen
- & Allan Bradley
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Article
| Open AccessBRD4 promotes resection and homology-directed repair of DNA double-strand breaks
BRD4 is a multifunctional regulator of chromatin binding that plays a direct role in DNA double-strand break repair. BRD4 interacts with the SWI/SNF chromatin remodeling complex and resection machinery to promote homologous recombination.
- John K. Barrows
- , Baicheng Lin
- & David T. Long
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Article
| Open AccessMutational landscape of normal epithelial cells in Lynch Syndrome patients
It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.
- Bernard C. H. Lee
- , Philip S. Robinson
- & Michael R. Stratton
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Article
| Open AccessMRNIP condensates promote DNA double-strand break sensing and end resection
The MRN complex is a critical sensor and processor of DNA double-strand breaks (DSBs). Here, the authors show that MRNIP forms liquid-like condensates to accelerate the MRN-mediated sensing and end resection of DSB, thereby promoting DSB repair.
- Yun-Long Wang
- , Wan-Wen Zhao
- & Xiang-Bo Wan
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Article
| Open AccessRad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase
Joseph et al. reveal that monoSUMOylated DDK kinase, implicated in replication initiation, acts with Rad51 recombinase to prevent replication fork uncoupling and to mediate recombination-dependent gap-filling in the presence of genotoxic stress.
- Chinnu Rose Joseph
- , Sabrina Dusi
- & Dana Branzei
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Article
| Open AccessMre11-Rad50 oligomerization promotes DNA double-strand break repair
The Mre11-Rad50 (MR) complex has key functions in the detection, signaling and repair of DNA breaks. Here the authors use transmission electron microscopy to show MR oligomerization is governed by a small beta-sheet protruding from the head domain of Rad50 at the base of the MR structure, and reveal MR head domain oligomerization is required for efficient DNA end resection.
- Vera M. Kissling
- , Giordano Reginato
- & Matthias Peter
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Article
| Open AccessBloom helicase mediates formation of large single–stranded DNA loops during DNA end processing
Bloom syndrome is a genetic disorder associated with increased cancer risk and is caused by mutations in Bloom helicase. This study investigates the mechanisms used by BLM helicase as initiates the repair of broken chromosomes.
- Chaoyou Xue
- , Sameer J. Salunkhe
- & Eric C. Greene
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Article
| Open AccessA POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation
DNA Double Strand breaks in transcriptionally active loci (TC-DSBs) undergo a dedicated repair pathway. Here, the authors show that excessive RNA:DNA hybrid accumulation at TC-DSBs elicits POLD3/BLM-dependent DNA synthesis that induces cell toxicity.
- S. Cohen
- , A. Guenolé
- & G. Legube
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Article
| Open AccessPervasive Transcription-coupled DNA repair in E. coli
Transcription-Coupled DNA repair has been classically defined as the preferential repair of the template strand (TS) over the non-template strand (NTS). Here the authors challenge this classic model of TCR by using a genome-wide repair assay, CPD-seq, as well as RNA-seq, to show that TCR occurs across the entire E. coli genome – including NTS and intergenic regions.
- Britney Martinez
- , Binod K. Bharati
- & Evgeny Nudler
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| Open AccessHarnessing DSB repair to promote efficient homology-dependent and -independent prime editing
Prime editing is a next-generation approach for precision genome engineering. Here the authors design a nuclease-based prime editor that leverages DNA repair pathways for targeted genomic insertions.
- Martin Peterka
- , Nina Akrap
- & Marcello Maresca
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Article
| Open AccessCas9 exo-endonuclease eliminates chromosomal translocations during genome editing
Chromosomal structural variations induced by CRISPR/Cas hinder its application in clinics. Here, the authors fuse Cas9 with optimized TREX2 to generate Cas9TX, which can prevent perfect repair and inhibit repeated cleavage.
- Jianhang Yin
- , Rusen Lu
- & Jiazhi Hu
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Article
| Open AccessCryo-EM structure of translesion DNA synthesis polymerase ζ with a base pair mismatch
The structure of mismatched DNA-Polζ ternary complex provides a basis for understanding what makes Polζ adept at extending DNA synthesis past mismatched base pairs.
- Radhika Malik
- , Robert E. Johnson
- & Aneel K. Aggarwal
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Article
| Open AccessRIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity
The 53BP1-RIF1 pathway is important for DNA repair. Here, the authors identified the histone chaperone ASF1, which functions as a suppressor of DNA end resection through changing high-order chromatin structure, as a partner of RIF1. This finding links DNA repair and dynamic changes of high-order chromatin structure.
- Sumin Feng
- , Sai Ma
- & Dongyi Xu
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Article
| Open AccessPrime editing efficiency and fidelity are enhanced in the absence of mismatch repair
Prime Editing is a versatile genome engineering tool. Here, the authors identify the DNA repair pathway known as mismatch repair as inhibitory for Prime Editing, thus, loss of mismatch repair enhances the efficiency of Prime Editing.
- J. Ferreira da Silva
- , G. P. Oliveira
- & J. I. Loizou
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Article
| Open AccessSomatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy
Here the authors show that elimination of germ cells carrying damaged genomes is regulated by intestinal stress signalling in nematodes. Failure of the intestinal signalling results in stress-induced aneuploidy indicating that environmental stress impacts inheritance.
- Najmeh Soltanmohammadi
- , Siyao Wang
- & Björn Schumacher
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Article
| Open AccessThe toposiomerase IIIalpha-RMI1-RMI2 complex orients human Bloom’s syndrome helicase for efficient disruption of D-loops
Human Bloom’s syndrome (BLM) helicase has a role in DNA repair, and BLM deficiency in humans is associated with chromosomal abnormalities. Here the authors employ solution biophysical assays to show BLM maintains a balance for disruption and stabilization of oligonucleotide-based D-loops. Interaction with the Topoisomerase IIIalpha-RMI1-RMI2 complex orients the activity toward D-loop disruption.
- Gábor M. Harami
- , János Pálinkás
- & Mihály Kovács
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| Open AccessDeciphering the mechanism of processive ssDNA digestion by the Dna2-RPA ensemble
RPA protects the integrity of single stranded DNA during DNA repair processes. Here the authors show how RPA actively participates in DNA transactions through its interactions with the endonuclease Dna2.
- Jiangchuan Shen
- , Yiling Zhao
- & Hengyao Niu
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Article
| Open AccessLinking DNA repair and cell cycle progression through serine ADP-ribosylation of histones
Poly(ADP-ribose)-polymerases (PARPs) are a cornerstone of the DNA damage response that promote DNA repair by modifying target proteins with ADP-ribose. Here, the authors show serine ADP-ribosylation of the H3 variant H3b maintains genome stability by coupling DNA repair with mitotic entry in Dictyostelium by regulating double strand break repair by nonhomologous end-joining (NHEJ).
- Julien Brustel
- , Tetsuya Muramoto
- & Nicholas D. Lakin
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| Open AccessBRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1
Loss of BRCA1 or BRCA2 results in genomic instability; however most studies have focused on the role of these proteins in double-strand break repair. Here the authors coupled cell line genetics and whole genome sequencing to investigate the formation of base substitutions and short indels in BRCA1-deficient cells, revealing a role for translesion DNA synthesis regulated by 53BP1.
- Dan Chen
- , Judit Z. Gervai
- & Dávid Szüts
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Article
| Open AccessTopoisomerase I (TOP1) dynamics: conformational transition from open to closed states
Topoisomerase I (TOP1) relaxes both positive and negative supercoils by nicking DNA and after rotation of the broken DNA strand closes the nick. Here, the authors present the DNA free crystal structure of TOP1 from the hyperthermophilic archaeon Caldiarchaeum subterraneum in the open form and discuss the mechanism of how DNA enters the catalytic site of TOP1.
- Diane T. Takahashi
- , Danièle Gadelle
- & Claudine Mayer
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Article
| Open AccessR-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability
Transcription can pose a threat to genomic instability through the formation of R-loops, which are RNA–DNA hybrids with a displaced non-template DNA strand. Here the authors mapped the R-loop proximal proteome in human cells and identified a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in gene promoters.
- Thorsten Mosler
- , Francesca Conte
- & Petra Beli
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Article
| Open AccessHelicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications
Microhomology-mediated end-joining (MMEJ) is a poorly defined mutagenic DNA break repair pathway. Here the authors show that the helicase HELQ is essential for polymerase theta-independent MMEJ, single-strand annealing and homologous recombination through synthesis dependent strand annealing in C. elegans.
- J. A. Kamp
- , B. B. L. G. Lemmens
- & M. Tijsterman
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Article
| Open AccessMechanism of Rad26-assisted rescue of stalled RNA polymerase II in transcription-coupled repair
Here the authors provide models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in different nucleotide states; explain how Rad26 domain motions help the polymerase progress past DNA lesions; and interpret the effects of CSB-associated disease mutations.
- Chunli Yan
- , Thomas Dodd
- & Ivaylo Ivanov
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Article
| Open AccessStructural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites
Microbial DNA glycosylases associated with the biosynthesis of DNA-damaging antibiotics have evolved self-resistance for their cognate natural products. Here, the authors provide evidence that cellular self-resistance is enabled by reduced affinity of the glycosylases for the excision products of the corresponding DNA lesions.
- Elwood A. Mullins
- , Jonathan Dorival
- & Brandt F. Eichman
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Article
| Open AccessMechanistic and genetic basis of single-strand templated repair at Cas12a-induced DNA breaks in Chlamydomonas reinhardtii
Single-stranded oligodeoxynucleotides are often used as templates for DNA repair during genome editing. Here the authors show that, unlike in animals, single-strand templated DNA repair in Chlamydomonas reinhardtii relies on the alternative end-joining enzyme polymerase θ.
- Aron Ferenczi
- , Yen Peng Chew
- & Attila Molnar
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Article
| Open AccessRNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination
BRCA1 dysfunction sensitizes cancer cells to PARP inhibitors (PARPi) but the underlying mechanism is unclear. Here, the authors identify RNF19A as a determinant of PARPi sensitivity, showing that RNF19A ubiquitinates BARD1, negatively regulates the BRCA1-BARD1 complex, and inhibits homologous recombination.
- Qian Zhu
- , Jinzhou Huang
- & Zhenkun Lou
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Article
| Open AccessZinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining
Classical non-homologous end-joining (cNHEJ) is the dominant pathway used by human cells to repair DNA double-strand breaks (DSBs) and maintain genome stability. Here the authors show that PARP1-driven chromatin expansion allows the recruitment of ZNF384, which in turn recruits Ku70/Ku80 to facilitate cNHEJ.
- Jenny Kaur Singh
- , Rebecca Smith
- & Haico van Attikum
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Article
| Open AccessA modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes
Ubiquitin (Ub) and Ub-like modifiers (Ubls) can form chains of various topologies, but preparing defined chains for functional studies remains challenging. Here, the authors develop chemoenzymatic tools to tailormake Ub/Ubl chains and study the involvement of specific Ub/SUMO chains in DNA repair.
- Maximilian Fottner
- , Maria Weyh
- & Kathrin Lang
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Article
| Open AccessSPINDOC binds PARP1 to facilitate PARylation
SPINDOC is known to interact with Spindlin1 (SPIN1), a histone code effector protein. Here, the authors show that SPINDOC is distributed between two distinct protein complexes, one comprising SPIN1 and the other one with PARP1. Their results suggest a role for SPINDOC in the regulation of PARP1- mediated PARylation and the DNA damage response.
- Fen Yang
- , Jianji Chen
- & Mark T. Bedford
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Article
| Open AccessArginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair
Post-translational modifications are critical for regulating the DNA damage response. Here, the authors identify a methylation-deubiquitination crosstalk between methyltransferase PRMT1 and deubiquitinase USP11, showing that the enzymes regulate each other’s functions in DNA repair.
- Maria Pilar Sanchez-Bailon
- , Soo-Youn Choi
- & Clare C. Davies
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Article
| Open AccessA non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is normally induced by innate immunity sensing for protection from pathogens. Here the authors show that cGAMP is also upstream of DNA damage signaling by activating ATM-CHK2-mediated repair pathway, while simultaneously suppressing the homology-directed repair.
- Daipayan Banerjee
- , Kurt Langberg
- & Nagaraj Kerur
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Article
| Open AccessADAR-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair
Different roles of specific RNA-related factors in DNA repair have now been reported. Here the authors reveal a role for RNA-editing by ADAR in DNA end resection following double strand break formation and a change in pattern of ADAR2-mediated A-to-I editing.
- Sonia Jimeno
- , Rosario Prados-Carvajal
- & Pablo Huertas