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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 AccessEngineering intelligent chassis cells via recombinase-based MEMORY circuits
The unification of decision-making, communication, and memory would enable the programming of intelligent biotic systems. Here, the authors achieve this goal by engineering E. coli chassis cells with an array of inducible recombinases that mediate diverse genetic programs.
- Brian D. Huang
- , Dowan Kim
- & Corey J. Wilson
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Article
| Open AccessGRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer
GRB2 is known for its role in Receptor Tyrosine Kinase and RAS signaling. Here the authors unveil a GRB2 function and mechanism for DNA replication fork protection. GRB2 alleviates oncogenic replication stress, and in doing so, averts cancer immune destruction by inhibiting cGAS/STING and pro-inflammatory cytokine production.
- Zu Ye
- , Shengfeng Xu
- & Zamal Ahmed
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Article
| Open AccessThe separation pin distinguishes the pro– and anti–recombinogenic functions of Saccharomyces cerevisiae Srs2
Here the authors report that the main role of the protein Srs2 in homologous recombination is to remove Rad51 from single stranded DNA, rather than to drive synthesis-dependent strand annealing.
- Aviv Meir
- , Vivek B. Raina
- & Eric C. Greene
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Article
| Open AccessMechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting
What underlies the synthetic lethality between BRCA1/2 or 53BP1 loss and Polθ loss is unclear. Here, the authors show that RPA-RAD52-MRE11 drive lethality when Polθ is absent in these cells. In BRCA1/2-deficient cells, sensitivity to Polθ inhibition additionally depends on the inhibited protein.
- George E. Ronson
- , Katarzyna Starowicz
- & Joanna R. Morris
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Article
| Open AccessGene duplication and deletion caused by over-replication at a fork barrier
Gene duplications and deletions are important drivers of evolution and disease. Here, the authors show that excess DNA generated at a replication fork barrier can be integrated at a new genomic site causing both a gene duplication and a deletion.
- Judith Oehler
- , Carl A. Morrow
- & Matthew C. Whitby
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Article
| Open AccessDouble-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ-dependent mechanism
Inverted duplications are a type of chromosome rearrangement observed in cancers. Here the authors show that a DNA double-strand break induces high frequency inverted duplications in cells lacking Mre11 nuclease by DNA polymerase δ-dependent mechanism.
- Amr M. Al-Zain
- , Mattie R. Nester
- & Lorraine S. Symington
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Article
| Open AccessFIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination
Assembly and disassembly of RAD51/DMC1 during homologous recombination are tightly regulated. Here, the authors show that the FIGNL1 ATPase limits non-productive assembly of RAD51/DMC1 on single-stranded and double-stranded DNAs during meiosis.
- Masaru Ito
- , Asako Furukohri
- & Akira Shinohara
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Article
| Open AccessThe RNA m5C modification in R-loops as an off switch of Alt-NHEJ
Here the authors show that DNA damage induced RNA m5C in R-loops competes with PARP1- mediated PARylation in transcribed genomes to promote cell survival which could be targeted be in cancer therapy.
- Haibo Yang
- , Emily M. Lachtara
- & Li Lan
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Article
| Open AccessStructure-forming CAG/CTG repeats interfere with gap repair to cause repeat expansions and chromosome breaks
Exposure of a structure-forming sequence within a single-stranded gap creates a fragile site, resulting in large deletions. Gap filling drives disease-causing CAG repeat expansions, with direction of instability determined by the identity of the sequence on the template strand of the gap.
- Erica J. Polleys
- , Isabella Del Priore
- & Catherine H. Freudenreich
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Article
| Open AccessPrime editing with genuine Cas9 nickases minimizes unwanted indels
Cas9 nickases (nCas9s) produce nicks or single-strand breaks in the DNA. Here the authors analyse the on- and off-target nicks generated by these nickases, and show that nCas9 (H840A) but not nCas9 (D10A) can cleave both strands and produce unwanted DNA double-strand breaks.
- Jaesuk Lee
- , Kayeong Lim
- & Jin-Soo Kim
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Article
| Open AccessStructural basis of Ty1 integrase tethering to RNA polymerase III for targeted retrotransposon integration
Cryo-EM structures of Ty1 integrase-Pol III complexes reveal determinants of Ty1 targeting upstream of Pol III-transcribed genes, and a functional impact of the integrase on Pol III activity that may increase the probability of Ty1 integration.
- Phong Quoc Nguyen
- , Sonia Huecas
- & Carlos Fernández-Tornero
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| Open AccessRad52’s DNA annealing activity drives template switching associated with restarted DNA replication
The restart of collapsed replication forks is associated with high rates of genomic rearrangement. Here, the authors show that during restart initiation rearrangements are driven mainly by Rad51, whereas during elongation they rely more on Rad52.
- Anastasiya Kishkevich
- , Sanjeeta Tamang
- & Matthew C. Whitby
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Article
| Open AccessTOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks
TOPOVIBL and REC114 are required for meiotic DNA double-strand breaks (DSBs). This study shows that TOPOVIBL forms a complex with REC114 and mice carrying mutations that disrupt the interaction show DSB defects with distinct outcomes in males and females.
- Alexandre Nore
- , Ariadna B. Juarez-Martinez
- & Bernard de Massy
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Article
| Open AccessStructural insight into Tn3 family transposition mechanism
Here the structure of transposase from Tn3 family is reported in apo form and bound to the transposon ends. The activation of the transposase induces metamorphic refolding of the catalytic domain suggesting the family-specific regulation mechanism.
- Alexander V. Shkumatov
- , Nicolas Aryanpour
- & Rouslan G. Efremov
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Article
| Open AccessJoint control of meiotic crossover patterning by the synaptonemal complex and HEI10 dosage
During meiosis, the number and distribution of crossovers (COs) are tightly controlled, but the mechanistic basis of this control is unclear. Here, by combining experimental data and mathematical modeling, the study advocates a CO patterning model via coarsening through the diffusion of HEI10 along the synaptonemal complex.
- Stéphanie Durand
- , Qichao Lian
- & Raphael Mercier
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Article
| Open AccessRedβ177 annealase structure reveals details of oligomerization and λ Red-mediated homologous DNA recombination
Redβ annealase catalyses single-strand annealing homologous DNA recombination. Here, the authors present a cryo-EM structure of a Redβ annealing intermediate bound to two complementary 27mer oligonucleotides.
- Timothy P. Newing
- , Jodi L. Brewster
- & Gökhan Tolun
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Article
| Open AccessRtt105 regulates RPA function by configurationally stapling the flexible domains
The single stranded DNA binding protein RPA coordinates DNA metabolism using multiple protein and DNA interaction domains. Here, the authors show that the chaperone-like protein Rtt105 staples RPA domains to prevent untimely protein interactions.
- Sahiti Kuppa
- , Jaigeeth Deveryshetty
- & Edwin Antony
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Article
| Open AccessModel-guided engineering of DNA sequences with predictable site-specific recombination rates
Site-specific recombination (SSR) is an important tool in synthetic biology, but its applications are limited by the inability to predictably tune SSR reaction rates. Here, using quantitative high-throughput experiments and machine learning, the authors achieve rational control of a DNA attachment site sequence to predictably modulate site-specific recombination rates both in vitro and in cells.
- Qiuge Zhang
- , Samira M. Azarin
- & Casim A. Sarkar
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| 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 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 AccessA point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats
HIV-1 integration sites are biased towards actively transcribed genes, likely mediated by binding of the viral integrase (IN) protein to host factors. Here, Winans et al. show that the K258R point mutation in IN eredirects viral DNA integration to the centromeres of host chromosomes, which may affect HIV latency.
- Shelby Winans
- , Hyun Jae Yu
- & Stephen P. Goff
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Article
| Open AccessRad52 mediates class-switch DNA recombination to IgD
IgD is expressed, predominantly together with IgM, via mRNA alternative splicing, but IgD class switch recombination (IgD CSR) has also been reported. Here the authors show, using Rad52-deficient mouse and human B cells, that IgD CSR is mediated by Rad52 through an alternative, microhomology-based end-joining pathway of DNA repair.
- Yijiang Xu
- , Hang Zhou
- & Paolo Casali
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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 AccessBRCA2 binding through a cryptic repeated motif to HSF2BP oligomers does not impact meiotic recombination
BRCA2 and its interactor HSF2BP are required for meiotic recombination. Here, the authors define the interaction structurally, revealing that a repeat in BRCA2 binds two HSF2BP units, increasing the affinity. This region is, however, not essential for mouse meiosis.
- Rania Ghouil
- , Simona Miron
- & Alex N. Zelensky
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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 AccessSmc5/6 functions with Sgs1-Top3-Rmi1 to complete chromosome replication at natural pause sites
Smc5/6, part of the structural maintenance of chromosomes (SMC) family, plays roles in genome structural integrity. Here the authors reveal that Smc5/6 acts jointly with Top3 within the STR complex to mediate DNA replication completion at genomic natural pausing sites (NPSs).
- Sumedha Agashe
- , Chinnu Rose Joseph
- & Dana Branzei
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Article
| Open AccessPh2 encodes the mismatch repair protein MSH7-3D that inhibits wheat homoeologous recombination
In the allohexaploid genome of wheat, meiotic recombination between homoeologues is suppressed through the action of several loci. Here, the authors report the cloning of the long sought-after gene Ph2 and show its function in reduction of homoeologous recombination.
- Heïdi Serra
- , Radim Svačina
- & Pierre Sourdille
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Article
| Open AccessMus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity
Mus81-Mms4 endonuclease is critical for processing various DNA recombination structures. Here the authors uncover a regulatory mechanism of the endonuclease via posttranslational modifications involving SUMOylation and ubiquitylation that impact on genome integrity.
- Anja Waizenegger
- , Madhusoodanan Urulangodi
- & Dana Branzei
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Article
| Open AccessTelomere damage induces internal loops that generate telomeric circles
Extrachromosomal circular DNA made of telomeric repeats have been found to have an effect on telomere maintenance. By combining electron microscopy with a telomere purification procedure the authors identify damage-induced i-loops as a key intermediate in telomere circle formation.
- Giulia Mazzucco
- , Armela Huda
- & Ylli Doksani
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| Open AccessRepair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ
Depending on the cell cycle stage, cells can repair their genome via different pathways. Here the authors reveal mechanistic insights into repair of double strand breaks induced during G1 in an error-prone manner by Pol θ-dependent and PARP1-independent alt NHEJ during the SG2/M phases of the cell cycle
- Wei Yu
- , Chloé Lescale
- & Ludovic Deriano
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| Open AccessA non-invasive far-red light-induced split-Cre recombinase system for controllable genome engineering in mice
Current light-inducible Cre-loxP systems have minimal capacity for deep tissue penetration. Here, the authors present a far-red light-induced split Cre-loxP system for in vivo genome engineering.
- Jiali Wu
- , Meiyan Wang
- & Haifeng Ye
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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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| 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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| Open AccessProline-rich protein PRR19 functions with cyclin-like CNTD1 to promote meiotic crossing over in mouse
Crossing over is a critical process during meiosis, although the regulation of this process still remains somewhat elusive. Here, the authors show that PRR19 partners with CNTD1 to enable formation of crossover-specific recombination complexes in mouse germ cells.
- Anastasiia Bondarieva
- , Kavya Raveendran
- & Attila Tóth
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Article
| Open AccessReal-time tracking reveals catalytic roles for the two DNA binding sites of Rad51
Rad51 drives DNA strand exchange, the central reaction in recombinational DNA repair. Two sites of Rad51 are responsible for DNA binding, but the function of these sites has proven elusive. Here, the authors employ real-time assays to reveal catalytic roles for the two DNA binding sites of Rad51.
- Kentaro Ito
- , Yasuto Murayama
- & Hiroshi Iwasaki
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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 AccessStructural insights into sequence-dependent Holliday junction resolution by the chloroplast resolvase MOC1
Holliday junctions (HJs) are DNA intermediates in genetic recombination that are resolved by nuclease, termed resolvase, to ensure genome stability. Here, the authors provide insights into the resolution process by resolving the crystal structure of the chloroplast resolvase MOC1 with HJs substrates.
- Junjie Yan
- , Sixing Hong
- & Ping Yin
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Article
| Open AccessATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis
Recombination requires DNA break formation by SPO11, following which SPO11 is thought to be released. Here, the authors show that meiotic hotspots retain SPO11 through a recombination intermediate dependent on the methyltransferase PRDM9, and that the ATM kinase governs the release of SPO11.
- Jacob Paiano
- , Wei Wu
- & André Nussenzweig
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Article
| Open AccessThe nuclear pore complex prevents sister chromatid recombination during replicative senescence
The Nuclear Pore Complex has been linked to DNA damage processing. Here the authors reveal that the Nup1 C-terminus is critical for the relocalization of eroded telomeres to nuclear pores and that modification of Nup1 promotes sister chromatid recombination and unleashes a new telomere maintenance mechanism.
- Paula Aguilera
- , Jenna Whalen
- & Vincent Géli
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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 AccessA ‘parameiosis’ drives depolyploidization and homologous recombination in Candida albicans
Mating of Candida albicans produces tetraploid products that return to the diploid state via a non-meiotic process known as concerted chromosome loss (CCL). Here, Anderson et al. show high recombination rates during CCL and identify factors that are essential for chromosome stability and recombination during CCL.
- Matthew Z. Anderson
- , Gregory J. Thomson
- & Richard J. Bennett
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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
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Article
| Open AccessStimulation of CRISPR-mediated homology-directed repair by an engineered RAD18 variant
Manipulating DNA repair pathways can be used to improve the outcomes of CRISPR-based genome editing. Here the authors derive an enhanced RAD18 variant that suppresses 53BP1 recruitment to DNA double-strand breaks to enhance homology-mediated repair.
- Tarun S. Nambiar
- , Pierre Billon
- & Alberto Ciccia
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Article
| Open AccessReducing MSH4 copy number prevents meiotic crossovers between non-homologous chromosomes in Brassica napus
Non-homologous crossovers impair correct chromosome segregation in allopolyploids. Here the authors show that most non-homologous crossovers in Brassica napus arise from MSH4-dependent recombination and provide evidence that post-polyploidization reduction of MSH4 duplicate stabilizes meiosis.
- Adrián Gonzalo
- , Marie-Odile Lucas
- & Eric Jenczewski
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Article
| Open AccessHuman RAD51 paralogue SWSAP1 fosters RAD51 filament by regulating the anti-recombinase FIGNL1 AAA+ ATPase
RAD51 assembly on single-stranded DNAs is an important step in the homology-dependent repair of DNA damage. Here authors reveal a role for the human RAD51 paralogue, SWSAP1, as a regulator of RAD51 assembly, by antagonizing RAD51 remodeller, FIGNL1 AAA + ATPase.
- Kenichiro Matsuzaki
- , Shizuka Kondo
- & Akira Shinohara