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| Open AccessDbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
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Article
| Open AccessDevelopmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier
DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.
- Zhiqian Li
- , Lang You
- & Ethan Bier
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Article
| Open AccessStructural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining
Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double strand-break (DSB) repair, directly re-ligates broken DNA ends with minimal errors. In this study, the authors identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) that prioritize ligation and promote NHEJ fidelity.
- Benjamin M. Stinson
- , Sean M. Carney
- & Joseph J. Loparo
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Article
| Open AccessiMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis
DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
- Aldo S. Bader
- & Martin Bushell
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Article
| Open AccessTDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription
Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs single strand breaks (SSBs) generated by DNA topoisomerase I (TOP1). Here the authors show that TDP1 also repairs TOP1-induced double strand breaks (DSBs).
- Diana Rubio-Contreras
- & Fernando Gómez-Herreros
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Article
| Open AccessGenome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice
Deshpande et al show that MRN nuclease-dependent processing of DNA ends in human cells occurs at sites bound by DNA-PK. Chromatin immunoprecipitation analysis of DNA-PK, MRN, and CtIP supports a sequential model of pathway choice.
- Rajashree A. Deshpande
- , Alberto Marin-Gonzalez
- & Tanya T. Paull
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Article
| Open AccessRNAPII-dependent ATM signaling at collisions with replication forks
Deregulation of transcription by oncogenes leads to collisions of RNA Polymerase II (RNAPII) with DNA replication machinery (transcription-replication conflicts, TRCs). This study shows that RNAPII activates ATM kinase at TRCs providing a mechanism for replication fork stalling and ATM activation at TRCs.
- Elias Einig
- , Chao Jin
- & Nikita Popov
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| Open AccessTrim33 masks a non-transcriptional function of E2f4 in replication fork progression
Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.
- Vanessa Rousseau
- , Elias Einig
- & Nikita Popov
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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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| 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 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 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 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 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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| 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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| Open AccessComprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption
CRISPR-Cas12f nucleases can be effectively packaged into AAVs for gene therapy, but a systematic evaluation of editing outcomes is lacking. Here the authors perform a comprehensive assessment of 4 Cas12f proteins and compare to Cas9 and two Cas12a proteins at a number of sites.
- Changchang Xin
- , Jianhang Yin
- & Jiazhi Hu
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Article
| Open AccessMulti-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks
Correct repair of broken DNA molecules is required to prevent potentially oncogenic mutations. To study repair fidelity and mechanism, van de Kooij et al. developed single cell reporters that detect if DNA breaks are fixed by error-free or mutagenic repair.
- Bert van de Kooij
- , Alex Kruswick
- & Michael B. Yaffe
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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 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 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 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 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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| 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 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 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 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 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 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 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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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 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 AccessSmall molecule inhibition of ATM kinase increases CRISPR-Cas9 1-bp insertion frequency
The mutational outcome of CRISPR-Cas9 editing can be both predictable and targeted. Here the authors show that ATM inhibitor KU-60019 increases 1 bp insertions at the targeted locus.
- Heysol C. Bermudez-Cabrera
- , Sannie Culbertson
- & Richard I. Sherwood
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Article
| Open AccessNucleolar release of rDNA repeats for repair involves SUMO-mediated untethering by the Cdc48/p97 segregase
rDNA repeats residing in the nucleolus must be released to the nucleoplasm to allow repair by homologous recombination. Here the authors reveal insights into the molecular mechanism proposing that phosphorylation and SUMOylation of the rDNA-tethering complex facilitate the nucleolar release of damaged repeats to maintain genome integrity.
- Matías Capella
- , Imke K. Mandemaker
- & Sigurd Braun
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Article
| Open AccessSmall tandem DNA duplications result from CST-guided Pol α-primase action at DNA break termini
Error-prone repair of DNA double-strand breaks have been implied to cause cancer-associated genome alterations, but the mechanism of their formation remains unclear. Here the authors find that DNA polymerase α primase plays part in tandem duplication formation at CRISPR/Cas9-induced complementary 3′ ssDNA protrusions.
- Joost Schimmel
- , Núria Muñoz-Subirana
- & Marcel Tijsterman
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Article
| Open AccessAbraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage
Break-induced replication (BIR), a subtype of HR, is a mutagenic mechanism that leads to chromosome rearrangements. Here the authors reveal insights into the role of Abraxas in limiting excessive DNA end resection, R-loop accumulation and cells undergoing BIR-dependent mitotic DNA synthesis.
- Xiao Wu
- & Bin Wang
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Article
| Open AccessDistinct pathways of homologous recombination controlled by the SWS1–SWSAP1–SPIDR complex
Human SWS1, SWSAP1, and SPIDR interact with RAD51, a critical protein for homology-directed repair. Here the authors reveal roles for the mouse SWS1–SWSAP1–SPIDR complex in inter-homolog recombination, including during meiosis, and sister chromatid exchange in BLM helicase deficient cells.
- Rohit Prakash
- , Thomas Sandoval
- & Maria Jasin
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Article
| Open AccessDHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination
DHX9 is an RNA helicase involved in the processing of pre-mRNA during transcription. Here the authors reveal a role for DHX9 in the initiation of homologues recombination during the early steps of end-resection.
- Prasun Chakraborty
- & Kevin Hiom
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Article
| Open AccessNon-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance
The molecular mechanisms underlying cancer cell radioresistance need to be elucidated. In this study, the authors show that the microRNA biogenesis factor DGCR8 is stabilized by USP51 and ATM upon irradiation and by consequence it promotes the repair of DNA double-strand breaks and radioresistance by recruiting RNF168 to sites of damage.
- Qinglei Hang
- , Liyong Zeng
- & Li Ma
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Article
| Open AccessUPF1 promotes the formation of R loops to stimulate DNA double-strand break repair
R loops are formed when single-stranded RNA anneals to one strand of DNA, forming three-stranded structures containing DNA-RNA hybrids and the displaced non-template single-stranded DNA. Here the authors reveal that the DNA:RNA helicase UPF1 plays a role in promoting R loops formation at telomeric double strand breaks to stimulate DNA resection and repair.
- Greg H. P. Ngo
- , Julia W. Grimstead
- & Duncan M. Baird
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Article
| Open AccessMitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo
Heteroplasmic mitochondrial DNA mutations lack effective treatments. Here the authors adapt I-CreI meganuclease to target the mitochondria and specifically-eliminate mtDNA with a m.5024C>T mutation in the mttRNA Ala gene.
- Ugne Zekonyte
- , Sandra R. Bacman
- & Carlos T. Moraes
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Article
| Open AccessSTING enhances cell death through regulation of reactive oxygen species and DNA damage
The endoplasmic reticulum-localized adaptor STING regulates the innate immune response through its ability to sense DNA damage. Here the authors reveal that STING functions as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
- Thomas J. Hayman
- , Marta Baro
- & Joseph N. Contessa
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Article
| Open AccessDNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells
Caspase independent alternative cell death (ACD) pathways exist, but have been largely investigated under non-physiological conditions. Here, the authors show that Drosophila primordial germ cells normally elicit DNase II-dependent DNA damage, triggering a parthanatos-like ACD pathway.
- Lama Tarayrah-Ibraheim
- , Elital Chass Maurice
- & Eli Arama
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Article
| Open AccessThe circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair
Cryptochrome 1 (CRY1) is a transcriptional coregulator associated with the circadian clock. Here the authors reveal that CRY1 is hormone-regulated, stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation.
- Ayesha A. Shafi
- , Chris M. McNair
- & Karen E. Knudsen
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Article
| Open AccessSpatiotemporal dynamics of 53BP1 dimer recruitment to a DNA double strand break
53BP1 is a crucial factor involved in double strand break repair which blocks DNA end resection affecting DNA repair pathway choice. Here the authors reveal by live cell nuclear architecture analysis the spatiotemporal dynamics of 53BP1 oligomerization during a DSB DNA damage response.
- Jieqiong Lou
- , David G. Priest
- & Elizabeth Hinde
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Article
| Open AccessCHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks
Chromatin is dynamically remodeled in response to DNA damage in favour of repair. Here the authors reveal how the chromatin remodeler CHD7 and chromatin binding protein 53BP1 regulate distinct DNA repair pathways.
- Magdalena B. Rother
- , Stefania Pellegrino
- & Haico van Attikum