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| Open AccessSimultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing
Low efficiency of target DNA integration remains a challenge in genome engineering. Here the authors perform large-scale compound library and genetic screens to identify targets that enhance gene editing: they see that combined DNA-PK and Polϴ inhibition with potent compounds increases editing efficiency and precision.
- Sandra Wimberger
- , Nina Akrap
- & Marcello Maresca
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Article
| Open AccessRAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles
In this study, the authors present structures and functional analyses for the RAD51C-XRCC3 tumor suppressor complex, providing insights into recurrent mutations in cancer and Fanconi Anemia patients that uncover distinct DNA replication fork protection, restart and reversal regions.
- Michael A. Longo
- , Sunetra Roy
- & Katharina Schlacher
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Article
| Open AccessAge-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis
The incidence of rheumatoid arthritis (RA) and accumulation of circulating free (cf) DNA increase with age but it is unknown whether DNA fragments cause joint inflammation. Here authors show that cf DNA levels are higher in RA patients and that in a rat adjuvant-induced arthritis model, the exonuclease TREX1 suppresses synovial inflammation via promoting the degradation of cf DNA and inhibiting a senescence-like cellular state.
- Wei-Dan Luo
- , Yu-Ping Wang
- & Vincent Kam Wai Wong
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Article
| Open AccessRegulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3
Here the authors identify that PARP1 maintains genome integrity by regulating replication fork recovery by break-induced replication. Mechanistically, this is achieved through MRE11-dependent PARP1 activation and site-specific ADP-ribosylation of PolD3.
- Frederick Richards
- , Marta J. Llorca-Cardenosa
- & Nicholas D. Lakin
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Article
| Open AccessMutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.
- Sujath Abbas
- , Oriol Pich
- & Maria Secrier
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Article
| Open AccessCell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9
ON-target genotoxicity in gene editing is generally underestimated. Here the authors report Fluorescence-Assisted Megabase-scale Rearrangements Detection (FAMReD) systems to detect and characterize rare large loss of heterozygosity: they show that ON-target genotoxicity can be prevented by p53 and cell cycle arrest.
- G. Cullot
- , J. Boutin
- & A. Bedel
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Article
| Open AccessASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
- Corina Maritz
- , Reihaneh Khaleghi
- & Hanspeter Naegeli
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| Open AccessTargeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open AccessSerine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling
In the DNA damage response, ADP-ribosylation is an essential signaling pathway. Here the authors utilize a multidisciplinary approach to establish its molecular basis in fruit flies and provide evidence for Drosophila’s suitability as model organism.
- Pietro Fontana
- , Sara C. Buch-Larsen
- & Ivan Ahel
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Article
| Open AccessBre1/RNF20 promotes Rad51-mediated strand exchange and antagonizes the Srs2/FBH1 helicases
Here the authors report that the yeast ubiquitin E3 ligase Bre1 and its human homolog RNF20 function as recombination mediator proteins by promoting Rad51-ssDNA assembly, Rad51 replacement of ssDNA-bound RPA while antagonizing the activities of Srs2 or FBH1 anti-recombinase.
- Guangxue Liu
- , Jimin Li
- & Xuefeng Chen
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Article
| Open AccessDynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases
The study unveils the structure, dynamics and regulatory mechanisms of the TFIIH protein assembly underpinning its divergent functions in gene expression and genome maintenance. Models link positions of TFIIH mutations to genetic disease phenotypes.
- Jina Yu
- , Chunli Yan
- & Ivaylo Ivanov
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Article
| Open AccessCdc14 phosphatase counteracts Cdk-dependent Dna2 phosphorylation to inhibit resection during recombinational DNA repair
Phosphorylation of Dna2 by the CDK stimulates resection of DNA double-strand breaks to stimulate recombinational DNA repair. Here the authors show that once resection has taken place, mitotically activated Cdc14 phosphatase inhibits resection by dephosphorylating Dna2 to facilitate DNA repair by homologous recombination.
- Adrián Campos
- , Facundo Ramos
- & Andrés Clemente-Blanco
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Article
| Open AccessReplication fork binding triggers structural changes in the PriA helicase that govern DNA replication restart in E. coli
The mechanism of replication restart initiation by the bacterial DNA replication restart proteins PriA and PriB is resolved, revealing a switch-like restructuring of PriA triggered by replication fork binding that mediates PriA/PriB complex assembly.
- Alexander T. Duckworth
- , Peter L. Ducos
- & James L. Keck
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Article
| Open AccessGenomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients
Xeroderma pigmentosum (XP) is a rare genetic disorder that is associated with a higher risk of skin cancer. Here, the authors analyse the genomes of skin cancers from patients across five different XP groups, revealing genetic and molecular factors related to the mutational profile and UV-related mutagenesis in XP.
- Andrey A. Yurchenko
- , Fatemeh Rajabi
- & Sergey I. Nikolaev
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Article
| Open AccessPathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity
Here the authors demonstrate that remodelling of perturbed replication forks by the exonuclease EXD2 modulates pathway choice within the Alternative Lengthening of Telomeres mechanism and identify potentially clinically important synthetic lethal interactions in ALT cancer cells.
- Ronan Broderick
- , Veronica Cherdyntseva
- & Wojciech Niedzwiedz
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Article
| Open AccessIntegrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
The causes of ALS remain unclear with many proposed pathomechanisms. Here, the authors integrate iPSC-derived motor neuron and post-mortem datasets and identify a heightened DNA damage response accompanied by accumulation of somatic mutations in ALS.
- Oliver J. Ziff
- , Jacob Neeves
- & Rickie Patani
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Article
| Open AccessHomology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1
The telomere binding proteins RAP1 and TRF2 protect telomeres from engaging in homology directed repair (HDR). In this study, the authors reveal that the basic domain of TRF2 (TRF2B) and RAP 1 cooperate to repress HDR at telomeres and prevent formation ultrabright telomere structures.
- Rekha Rai
- , Kevin Biju
- & Sandy Chang
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Article
| Open AccessRestoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response
Aging is associated with a loss of blood stem cell fitness in part due to defects in stem cell-supportive niches. Here, the authors demonstrate that restoring niche function by treatment with Netrin-1 is able to rejuvenate aged blood stem cells.
- Pradeep Ramalingam
- , Michael C. Gutkin
- & Jason M. Butler
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Article
| Open AccessReplication-associated formation and repair of human topoisomerase IIIα cleavage complexes
This study provides evidence that human topoisomerase IIIα (TOP3A) is closely associated with active replisomes. The authors uncover TOP3A DNA cleavage complexes (TOP3Accs) repair mechanisms to ensure normal DNA replication and genome integrity.
- Liton Kumar Saha
- , Sourav Saha
- & Yves Pommier
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Article
| Open AccessDNA double-strand break end synapsis by DNA loop extrusion
DNA double-strand breaks (DSBs) occur every cell cycle and must be repaired. Here the authors combine theory and simulations to establish a likely role for loop extrusion in bringing the DSB ends back into proximity for repair.
- Jin H. Yang
- , Hugo B. Brandão
- & Anders S. Hansen
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Article
| Open AccessSignalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)
The kinase inhibitor Ponatinib inhibits an ABL1-JUN signalling axis and alters telomere homeostasis, reduces telomere synthesis, and provokes telomere dysfunction in cancer cells which employ the alternative lengthening of telomeres mechanisms.
- Frances Karla Kusuma
- , Aishvaryaa Prabhu
- & Maya Jeitany
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Article
| Open AccessFarrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer
Here the authors find that farrerol directly binds to UCHL3 and activates its deubiquitinase activity, and that farrerol promotes development of SCNT embryos by enhancing HR repair and restoring epigenetic networks in a UCHL3-dependent manner.
- Weina Zhang
- , Mingzhu Wang
- & Ying Jiang
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Article
| Open AccessTRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks
The retention of 53BP1 at DNA double strand breaks (DSBs) is inhibitory to homologous recombination repair. Following ionising radiation, the authors demonstrate that TRABID-mediated deubiquitination of 53BP1 promotes its retention, sensitising prostate cancer to PARP inhibition.
- Jian Ma
- , Yingke Zhou
- & Lei Li
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Article
| Open AccessExcessive reactive oxygen species induce transcription-dependent replication stress
Excessive oxidative stress is widely perceived as a key factor in cancer progression. Here, the authors reveal that oxidative stress induces transcription-dependent replication fork stalling that appears to be a major source of chromosomal rearrangements found in human cancers.
- Martin Andrs
- , Henriette Stoy
- & Pavel Janscak
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Article
| Open AccessHistone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
Alternative lengthening of telomeres (ALT) provides cancer cells a mechanism to sustain replicative immortality. Here, the authors identify KDM2A as a molecular vulnerability in ALT-dependent cancer cells and demonstrate its role in the resolution of ALT-specific telomere clusters via recruitment of SENP6.
- Fei Li
- , Yizhe Wang
- & Hongwu Zheng
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Article
| Open AccessRETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
Polymerase (POL) θ inhibitors display synthetic lethality in tumours with homologous recombination repair deficiency. Here, the authors demonstrate that POLθ inhibition with novobiocin activates the cGAS/STING pathway in BRCA-deficient cancers.
- Jeffrey Patterson-Fortin
- , Heta Jadhav
- & Geoffrey I. Shapiro
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Article
| Open AccessShort-term molecular consequences of chromosome mis-segregation for genome stability
Chromosomal instability leads to aneuploidy, a state of karyotype imbalance. By inducing controlled chromosome mis-segregation, Santaguida and colleagues show that aneuploidy can also instigate chromosomal instability.
- Lorenza Garribba
- , Giuseppina De Feudis
- & Stefano Santaguida
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Article
| Open AccessDeacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance
The molecular mechanisms underlying acquired chemoresistance to proteasome inhibitors (PIs) in multiple myeloma (MM) remain to be explored. Here, the authors highlight the role of heterochromatin protein 1 gamma as a potential target for overcoming resistance to PIs in MM.
- Xin Li
- , Sheng Wang
- & Zhiqiang Liu
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Article
| Open AccessLimitations of gene editing assessments in human preimplantation embryos
DNA repair in response to DSBs in the preimplantation embryo is hard to analyze. Here the authors show that over 25% of pre-existing heterozygous loci in control single blastomere samples appeared as homozygous after whole genome amplification, therefore, they validated gene editing seen in human embryos in ESCs.
- Dan Liang
- , Aleksei Mikhalchenko
- & Shoukhrat Mitalipov
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Article
| Open AccessLoss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage
Thyroid hormones have an important role in fostering tumour progression, however their upstream regulators are less clear. Here, the authors identify the thyroid hormone activating enzyme type 2 deiodinase as a p53 target gene and demonstrate its contribution to tumour progression in p53 mutant squamous cell carcinoma.
- Annarita Nappi
- , Caterina Miro
- & Monica Dentice
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Article
| Open AccessGenetic requirements for repair of lesions caused by single genomic ribonucleotides in S phase
RNase H2 removes mutagenic rNMPs from genomic DNA. The authors demonstrate how nicked rNMPs are repaired when they are encountered in S phase. This study unveils genetic interactions that could potentially be exploited in RNase H2-deficient pathologies.
- Natalie Schindler
- , Matthias Tonn
- & Brian Luke
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Article
| Open AccessSystematically attenuating DNA targeting enables CRISPR-driven editing in bacteria
Genome editing in bacteria normally requires efficient recombination and high transformation efficiencies, which often isn’t. Here the authors report that systematically attenuating DNA targeting activity enables RecA-mediated repair in different bacteria, allowing chromosomal cleavage to drive editing.
- Daphne Collias
- , Elena Vialetto
- & Chase L. Beisel
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Article
| Open AccessAntecedent chromatin organization determines cGAS recruitment to ruptured micronuclei
DNA damage-induced micronuclei are linked to downstream viral signalling through the cGAS pattern recognition receptor. Here, the authors identify features of micronuclei chromatin that determine cGAS-MN recruitment and associated pathway activation.
- Kate M. MacDonald
- , Shirony Nicholson-Puthenveedu
- & Shane M. Harding
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Article
| Open AccessReplication gap suppression depends on the double-strand DNA binding activity of BRCA2
Here the authors demonstrate that the dsDNA binding function at the N-terminus of BRCA2 prevents nucleotide depletion-dependent replicative ssDNA gaps but not those induced by PARP inhibition. This function is impaired in breast-cancer variants affecting this region.
- Domagoj Vugic
- , Isaac Dumoulin
- & Aura Carreira
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Article
| Open AccessDNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation
Exon 27 of the tumor suppressor BRCA2 encodes a portion of the protein crucial for DNA repair, genome maintenance, and tumor suppression. Here the authors show that this domain binds DNA and the RAD51 recombinase to enhance the assembly of RAD51-DNA complexes.
- Youngho Kwon
- , Heike Rösner
- & Patrick Sung
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Article
| Open AccessA CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene
Formaldehyde can trigger formation of interstrand crosslinks (ICLs) or DNA-protein crosslinks (DPCs) leading to genome instability. Here the authors show that EXO1 limits replication stress and DNA damage to counteract formaldehyde-induced genome instability.
- Yuandi Gao
- , Laure Guitton-Sert
- & Jean-Yves Masson
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Article
| Open AccessSPRTN patient variants cause global-genome DNA-protein crosslink repair defects
DNA-protein crosslinks (DPCs) are toxic DNA lesions which threaten genome stability. Here, the authors develop a method to track the fate of DPCs in cells and identify a role for the SPRTN protease in replication-independent DPC repair.
- Pedro Weickert
- , Hao-Yi Li
- & Julian Stingele
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Article
| Open AccessActive mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress
Here the authors show that the exonuclease EXD2 is involved in the recovery of class II gene transcription after UV irradiation. EXD2 travels from the mitochondria to the nucleus to interact with RNA Pol II and degrade new synthetized mRNA to allow transcription following DNA repair.
- Jérémy Sandoz
- , Max Cigrang
- & Frédéric Coin
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Article
| Open AccessDevelopment of a versatile nuclease prime editor with upgraded precision
Strategies to improve the specificity of nuclease-based prime editor (PEn) are needed. Here the authors report a 53BP1-inhibitory ubiquitin variant-assisted PEn platform (uPEn) to inhibit NHEJ and enable precise prime editing for generation of insertions, deletions and replacements.
- Xiangyang Li
- , Guiquan Zhang
- & Xingxu Huang
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Article
| Open AccessCRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
Identifying prostate cancer patients who may respond well to PARP inhibitors is important for their success in the clinic. Here, using a genome-wide CRISPR-Cas9 knockout screen, the authors identify MMS22L as a biomarker for sensitivity to PARP inhibition in BRCA1/2-proficient prostate cancer.
- Takuya Tsujino
- , Tomoaki Takai
- & Li Jia
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Article
| Open AccessArabidopsis γ-H2A.X-INTERACTING PROTEIN participates in DNA damage response and safeguards chromatin stability
γ-H2A.X is a critical signal for DNA double strand break responses. In this study, an Arabidopsis protein that interacts with γ-H2A.X and the recombinase RAD51 is shown to contribute to plant chromatin stability and integrity.
- Tianyi Fan
- , Huijia Kang
- & Yan Zhu
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Article
| Open AccessSafeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration
Undesired chromosomal translocations, vector integrations, and large deletions remain a problem for therapeutic gene editing in vivo. Here, the authors compare the CRISPR-Cas9TX variant with CRISPR-Cas9 and show elimination of chromosomal translocations and reduction of AVV integration when targeting Vegfa for the treatment of age-related macular degeneration in a mouse model.
- Jianhang Yin
- , Kailun Fang
- & Jiazhi Hu
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Article
| Open AccessCRISPR-Cas12a induced DNA double-strand breaks are repaired by multiple pathways with different mutation profiles in Magnaporthe oryzae
In this work, Huang and colleagues describe variation in DNA repair outcomes due to distinct repair mechanisms following CRISPR targeting of different loci in the plant pathogenic fungus Magnaporthe oryzae.
- Jun Huang
- , David Rowe
- & David E. Cook
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Article
| Open AccessStructural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus
Vaccinia virus expresses two proteins that interfere with the host immune response. Here, authors provide the structural basis for this viral defence mechanism, conserved in other poxviruses such as the causatives agents of smallpox and monkeypox.
- Angel Rivera-Calzada
- , Raquel Arribas-Bosacoma
- & Oscar Llorca
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Article
| Open AccessRegulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1
Aminoacyl-tRNA synthetases possess unique domains. In this study the structure of the vertebrate IARS1 and EARS1 complex reveals that vertebrate IARS1 protects the DNA repair factor BRCA1 from proteolytic degradation via its UBX-fold domain.
- Scisung Chung
- , Mi-Sun Kang
- & Yunje Cho
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Article
| Open AccessSAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks
SAMHD1 has a dNTPase-independent resection function in genome maintenance. Here the authors show that SAMHD1 is deacetylated at conserved K354 by SIRT1 to facilitate direct binding with ssDNA to promote DNA end resection and homologous recombination.
- Priya Kapoor-Vazirani
- , Sandip K. Rath
- & David S. Yu
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Article
| Open AccessA BDNF-TrkB autocrine loop enhances senescent cell viability
Selective elimination of senescent cells is an approach that has shown promise to ameliorate age-associated pathologies in preclinical models. Here the authors report that BDNF enhances senescent cell viability via TrkB in cultured cells, and that TrkB inhibition can reduce the accumulation of senescent cells in aged mouse organs.
- Carlos Anerillas
- , Allison B. Herman
- & Myriam Gorospe
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Article
| Open AccessSelective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair
Finding a selective modulator of Lys63-linked ubiquitin chains has proven very challenging. Here, the authors develop potent macrocyclic peptide binders of Lys63-linked di-ubiquitin chains that interrupt DNA damage repair and lead to apoptotic cell death.
- Ganga B. Vamisetti
- , Abhishek Saha
- & Ashraf Brik
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Article
| Open AccessISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress
DNA replication stress can result in genome instability. Here the authors show that the ubiquitin like modifier protein, ISG15, important during the innate immune response, acts at replication forks to mitigate DNA replication stress.
- Christopher P. Wardlaw
- & John H. J. Petrini