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| Open AccessFLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress
Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.
- Jessica D. Tischler
- , Hiroshi Tsuchida
- & Richard O. Adeyemi
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Article
| Open AccessPSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity
R-loop accumulation at transcription sites poses a persistent threat to genome integrity. Here the authors demonstrate a role for PSIP1/LEDGF protein in reducing R-loop levels at the site of transcription and preventing transcription replication conflict to maintain genome integrity.
- Sundarraj Jayakumar
- , Manthan Patel
- & Madapura M. Pradeepa
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| 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 AccessAlternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs
ALT cells use an alternative lengthening mechanism of telomeres and bear telomeric DNA damage with increased levels of damage-induced long non-coding RNA. Here the AUs show that antisense oligonucleotides (ASO) targeting such RNAs can induce ALT cancer cells selective cell death.
- Ilaria Rosso
- , Corey Jones-Weinert
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessStructural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2
Here the authors report the cryoEM structure of the RAD51 nucleoprotein filament bound to the C-terminal TR2 domain of BRCA2. The structure explains how BRCA2 stabilises the filament and uncovers a conserved mechanism of filament binding by recombination mediators.
- Robert Appleby
- , Luay Joudeh
- & Luca Pellegrini
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| Open AccessInducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells
Gene editing is still hampered by unintended genomic alterations. Here the authors propose a method for correcting heterozygous mutations that employs multiple nicks induced by Cas9 nickase and the homologous chromosome as an endogenous repair template (NICER): this rarely induces unintended genomic alterations.
- Akiko Tomita
- , Hiroyuki Sasanuma
- & Shinichiro Nakada
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Article
| Open AccessA RAD51–ADP double filament structure unveils the mechanism of filament dynamics in homologous recombination
RAD51 filaments are essential for eukaryotic homologous recombination. This study shows the cryo-EM structure of an ADP-bound RAD51 double-filament that wraps around ssDNA revealing a stepwise collapsing mechanism for the transition between the ATP/ADP-bound filament intermediates.
- Shih-Chi Luo
- , Min-Chi Yeh
- & Meng-Chiao Ho
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Article
| 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 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 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 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 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 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 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 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 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 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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| 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 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 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 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 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 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 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 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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Article
| 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 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 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 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 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 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
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Article
| Open AccessThe RAD51 recombinase protects mitotic chromatin in human cells
RAD51 is a well known player of DNA repair and homologous recombination. Here the authors reveal a function for RAD51 in protecting under-replicated DNA in mitotic human cells, promoting mitotic DNA synthesis (MiDAS) and successful chromosome segregation.
- Isabel E. Wassing
- , Emily Graham
- & Fumiko Esashi
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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 AccessSPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells
Cancer stem cells can evade treatment. Here, the authors perform an in vitro screen to identify proteins that are involved in protecting glioma cancer stem cells from therapy and find that SPT6 increases BRCA1 expression and drives error-free DNA repair, thereby ensuring the survival of the cells.
- Elisabeth Anne Adanma Obara
- , Diana Aguilar-Morante
- & Petra Hamerlik
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Article
| Open AccessSequential role of RAD51 paralog complexes in replication fork remodeling and restart
Replication stress has been associated with transient remodelling of replication intermediates into reversed forks, followed by efficient fork restart. Here the authors systematically analyse the role of RAD51 paralogs in these transactions, providing insights on the mechanistic role of different complexes of these proteins.
- Matteo Berti
- , Federico Teloni
- & Massimo Lopes
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Article
| Open AccessRad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases
In budding yeast, the 53BP1 ortholog Rad9 limits the resection nucleolytic processing of DNA double strand breaks. Here the authors reveal that Rad9 promotes long tract gene conversions, BIR and CO, during the HR repair of a DSB via modulation of Sgs1 and Mph1 helicases.
- Matteo Ferrari
- , Chetan C. Rawal
- & Achille Pellicioli
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Article
| Open AccessSpecificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
DNA double-strand break repair by homologous recombination initiates with nucleolytic resection of the 5’ DNA strand at the break ends. Here, the authors reveal that the lesion context influences the action and efficiency of the long range resection factors EXO1 and BLM-DNA2.
- James M. Daley
- , Nozomi Tomimatsu
- & Patrick Sung
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Article
| Open Accessm5C modification of mRNA serves a DNA damage code to promote homologous recombination
Post-translational modifications of proteins at DNA damage sites can facilitate the recruitment of DNA repair factors. Here, the authors show that mRNA is locally modified with m5C at sites of DNA damage by the RNA methyltransferase TRDMT1 to promote homologous recombination repair.
- Hao Chen
- , Haibo Yang
- & Li Lan
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Article
| Open AccessTimed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair
Altering cellular responses to double-strand breaks in DNA could rebalance CRISPRediting outcomes. Here, the authors use a pooled CRISPR screen to identify inhibition of CDC7 as a strategy to improve HDR outcomes.
- Beeke Wienert
- , David N. Nguyen
- & Jacob E. Corn
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Article
| Open AccessPALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1
Although loss of BRCA1 leads to defects in DNA double-strand break repair by homologous recombination (HR) and renders cells hypersensitive to PARP inhibitors, resistance to the drugs can arise. Here the authors reveal that PALB2 chromatin recruitment restores HR in BRCA1-deficient cells depleted of 53BP1.
- Rimma Belotserkovskaya
- , Elisenda Raga Gil
- & Stephen P. Jackson
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Article
| Open AccessDNA repair by Rad52 liquid droplets
Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.
- Roxanne Oshidari
- , Richard Huang
- & Karim Mekhail
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Article
| Open AccessRad50 zinc hook functions as a constitutive dimerization module interchangeable with SMC hinge
The Mre11/Rad50 complex, which functions in genome surveillance, possesses antiparallel coiled-coil arms forming a ring-like structure similar to that of the SMC family proteins. Here the authors find that the Rad50 zinc hook functions similarly to the hinge of the SMC protein, and that the ring structure of the Mre11/Rad50 dimer also opens by disconnecting its globular head domains.
- Hisashi Tatebe
- , Chew Theng Lim
- & Asako Furukohri
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Article
| Open AccessRpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion
Double strand breaks (DSBs) are preferentially repaired by sister-chromatid recombination (SCR) to maintain genome stability. Here, the authors reveal a role for histone deacetylate (HDAC) complexes favouring the repair of replication related DSBs by facilitating cohesin loading.
- Pedro Ortega
- , Belén Gómez-González
- & Andrés Aguilera
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Article
| Open AccessNon-enzymatic roles of human RAD51 at stalled replication forks
RAD51 has been implicated in replication fork processing and restart in response to replication stress. Here, authors reveal mechanistic aspects of non-enzymatic roles of RAD51 for fork reversal and cooperation with FBH1.
- Jennifer M. Mason
- , Yuen-Ling Chan
- & Douglas K. Bishop
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Article
| Open AccessIn vitro role of Rad54 in Rad51-ssDNA filament-dependent homology search and synaptic complexes formation
Homologous recombination uses a template to accurately repair DNA double-strand breaks and stalled replication forks to maintain genome stability. Here authors use electron microscopy to investigate the role of Rad54 in homology search and synaptic complex formation.
- Eliana Moreira Tavares
- , William Douglass Wright
- & Pauline Dupaigne
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Article
| Open AccessA high-resolution map of non-crossover events reveals impacts of genetic diversity on mammalian meiotic recombination
During meiotic recombination, genetic information is transferred or exchanged between parental chromosome copies. Using a large hybrid mouse pedigree, the authors generated high-resolution maps of these transfer/exchange events and discovered new properties governing their processing and resolution.
- Ran Li
- , Emmanuelle Bitoun
- & Simon R. Myers
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Article
| Open AccessThe Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway
The homologous recombination machinery needs to be recruited at replication intermediates for accurate functioning. Here, the authors reveal that a Rad51 paralog-containing complex, called the Shu complex, recognizes and enables tolerance of predominantly lagging strand abasic sites.
- Joel C. Rosenbaum
- , Braulio Bonilla
- & Kara A. Bernstein