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| 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
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Article
| Open AccessA meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination
Homology directed repair of meiotic double-strand breaks functions via recruitment and assembly of strand-exchange proteins called recombinases. Here the authors reveal and characterize a BRCA2 interactor regulating meiotic recombinases that localizes to chromosomal axes and facilitates the repair of meiotic DSBs.
- Jingjing Zhang
- , Yasuhiro Fujiwara
- & Hiroki Shibuya
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| Open AccessThe ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity
53BP1 is a key player in non-homologous end joining (NHEJ). Here the authors reveal an important role for the multifunctional homodimeric protein hub dynein light chain 1 (DYNLL1) in increasing the efficacy of 53BP1-mediated repair of DNA double-strand breaks (DSBs) by NHEJ.
- Jordan R. Becker
- , Raquel Cuella-Martin
- & J. Ross Chapman
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| Open AccessShu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination
Homologous recombination ensures genome integrity during meiotic recombination. Here the authors reveal that factors SWS1 and SWSAP1 are critical for meiotic homologues recombination, particularly in promoting assembly of RAD51 and DMC1 on early recombination intermediates.
- Carla M. Abreu
- , Rohit Prakash
- & Maria Jasin
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| Open AccessMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Around 10% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1 promoter methylation, but it is uncertain how it predicts response to PARP inhibition. Here, the authors show that homozygous BRCA1 methylation predicts response to rucaparib while heterozygous methylation of BRCA1 predicts resistance in HGSOC.
- Olga Kondrashova
- , Monique Topp
- & Clare L. Scott
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| Open AccessSpatiotemporal dynamics of homologous recombination repair at single collapsed replication forks
How factors involved in homologous recombination interact and function is a matter of interest. Here the authors use super-resolution imaging to describe the spatiotemporal dynamics of proteins associated with homologous recombination DNA repair in response to replication stress.
- Donna R. Whelan
- , Wei Ting C. Lee
- & Eli Rothenberg
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Article
| Open AccessGFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1
The transcription factor GFI1 mediates the DNA damage response (DDR) of T cells through a yet unknown mechanism. Here the authors show that GFI1 can adopt non-transcriptional roles during DDR, enabling PRMT1 to bind and methylate the DNA repair proteins MRE11 and 53BP1.
- Charles Vadnais
- , Riyan Chen
- & Tarik Möröy
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Article
| Open AccessMRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways
Bloom helicase is recruited to double strand breaks in an ATM dependent manner. Here the authors show that Bloom helicase is recruited to double strand breaks in an ATM and MRN dependent manner with HR and NHEJ regulated by the helicase depending on the phase of the cell cycle.
- Vivek Tripathi
- , Himanshi Agarwal
- & Sagar Sengupta
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Article
| Open AccessBLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes
Bloom syndrome is characterized by high levels of sister chromatid exchanges (SCEs). Here, the authors use single-cell DNA template strand-sequencing to map SCEs in patient cells, and propose that the BLM helicase protects the genome against unwanted recombination at sites of G-quadruplex structures.
- Niek van Wietmarschen
- , Sarra Merzouk
- & Peter M. Lansdorp
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Article
| Open AccessUSP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A
BRCA1 ligase activity is tightly regulated to maintain genome stability and confer DNA double strand repair. Here the authors identify USP48 as a H2A deubiquitinating enzyme that acts as a BRCA1 E3 ligase antagonist and characterize its role during DNA repair.
- Michael Uckelmann
- , Ruth M. Densham
- & Joanna R. Morris
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Article
| Open AccessATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice
Cockayne syndrome group B protein (CSB) is a multifunctional chromatin remodeler involved in double-strand break repair. Here the authors investigate the molecular post-translational signals regulating CSB activity.
- Nicole L. Batenburg
- , John R. Walker
- & Xu-Dong Zhu
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Article
| Open AccessReplication fork reversal triggers fork degradation in BRCA2-defective cells
BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.
- Sofija Mijic
- , Ralph Zellweger
- & Massimo Lopes
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Article
| Open AccessBRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination
BRCA2 mutations promote tumour formation while also paradoxically causing cell lethality. Here the authors generate conditional BRCA2 loss in a non-transformed human mammary cell line and see increased replication stress due to under-replication of DNA.
- Weiran Feng
- & Maria Jasin
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| Open AccessDNA end resection requires constitutive sumoylation of CtIP by CBX4
The choice between non-homologous end-joining and homologous recombination to repair a DNA double-strand break depends on activation of the end resection machinery. Here the authors show that SUMO E3 ligase CBX4 sumoylates subpopulation of CtIP to regulate recruitment to breaks and resection.
- Isabel Soria-Bretones
- , Cristina Cepeda-García
- & Pablo Huertas
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| Open AccessRobust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation
Mutations in homology-directed repair genes likeBRCA2are linked to breast cancer susceptibility. Here the authors generate mice with an inducible DNA break-reporter system and see high levels of homology-directed repair in proliferative mammary tissue and a general reliance on BRCA2 in various tissues.
- Elizabeth M. Kass
- , Pei Xin Lim
- & Maria Jasin
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Article
| Open AccessCoordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks
Homologous recombination requires end resection of the DNA at the site of the break, however the Ku dimer can sequester single-ended double-strand breaks. Here the authors show that ATM-dependent phosphorylation of CtIP, along with the actions of Mre11, impair the stable loading of Ku onto DNA.
- Pauline Chanut
- , Sébastien Britton
- & Patrick Calsou
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Article
| Open AccessCDK1 phosphorylates WRN at collapsed replication forks
End-resection of double strand DNA breaks is essential for pathway choice between non-homologous end-joining and homologous recombination. Here the authors show that phosphorylation of WRN helicase by CDK1 is essential for resection at replication-related breaks.
- Valentina Palermo
- , Sara Rinalducci
- & Pietro Pichierri
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Article
| Open AccessA second DNA binding site in human BRCA2 promotes homologous recombination
BRCA2 is a well-characterized central player in homologous recombination in which it functions as the RAD51 loader. Here the authors identify an N-terminal region of BRCA2 that binds DNA and promotes efficient DNA repair.
- Catharina von Nicolai
- , Åsa Ehlén
- & Aura Carreira
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| Open AccessCullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
CtIP has a key role in DNA double-strand break repair as its role in resecting DNA at the break commits a cell to homologous recombination. Here the authors show that KLHL15 interacts with CtIP and regulates repair by controlling protein turnover.
- Lorenza P. Ferretti
- , Sarah-Felicitas Himmels
- & Alessandro A. Sartori
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| Open AccessA genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection
A DNA double strand break can be repaired through either the non-homologous end-joining or the homologous recombination pathways. Here the authors conduct a genome-wide screen and identify a role for CCAR2 in pathway choice by regulating DNA end resection by CtIP.
- Ana López-Saavedra
- , Daniel Gómez-Cabello
- & Pablo Huertas
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| Open AccessSynthetic viability by BRCA2 and PARP1/ARTD1 deficiencies
The PARP inhibitor olaparib is an approved treatment method for women with BRCA1 and BRCA2 mutation associated cancers. Here the authors show that olaparib can contribute to synthetic viability of cells if PARP1 is inhibited before BRCA2 loss.
- Xia Ding
- , Arnab Ray Chaudhuri
- & Shyam K. Sharan
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| Open AccessHomologous recombination-dependent repair of telomeric DSBs in proliferating human cells
Telomeres protect the ends of chromosomes from the DNA damage recognition machinery, however how damage in telomeres is repaired is poorly understood. Here the authors use CRISPR-Cas9 to induce DNA breaks and identify proliferation dependent homologous recombination repair.
- Pingsu Mao
- , Jingfan Liu
- & Yong Zhao
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Article
| Open AccessCRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection
The repair of double-strand DNA breaks by homologous recombination requires resection of the DNA ends. Here the authors show that in Schizosaccharomyces pombe and human cells, Wdr70 is recruited as part of the CRL4 complex to promote ubiquitination of H2B and allow Exo1-mediated resection.
- Ming Zeng
- , Laifeng Ren
- & Cong Liu
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| Open AccessTRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions
While yeast Rap1 regulates telomere length and protects telomeres from non-homologous end joining, its role in higher eukaryotes is controversial. Here the authors present evidence that in mammals, RAP1 cooperates with TRF2 to prevent homologous recombination-mediated repair of telomeres.
- Rekha Rai
- , Yong Chen
- & Sandy Chang
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Article
| Open AccessTRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage
Recruiting DNA damage repair factors to the sites of DNA damage is critical for the maintenance of genome integrity. Here the authors identify that the TRAF-interacting protein (TRAIP/RNF206) is required for normal recruitment of RAP80 to DNA lesions and the stimulation of homologous recombination.
- Nam Soo Lee
- , Hee Jin Chung
- & Hongtae Kim
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| Open AccessPromotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52
Homologous repair of DNA double strand breaks in Saccharomyces cerevisiaeis dependent on several conserved Rad51 paralogs. Here the authors provide biochemical evidence that Rad55-Rad57 synergistically interacts with the Shu complex to promote Rad51 filament formation and homology directed repair.
- William A. Gaines
- , Stephen K. Godin
- & Kara A. Bernstein
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| Open AccessMCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex
The MCM8-9 complex is required for repair of DNA double-strand breaks (DSBs). Here, the authors show that MCM8-9 is required for the nuclease activity of the MRE11-RAD50-NBS1 complex (MRN) and stabilizes its association with DNA damage sites, promoting resection of DSB ends.
- Kyung Yong Lee
- , Jun-Sub Im
- & Anindya Dutta
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Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms
Structural variation is a major source of complexity in the human genome. Here Abyzov et al.present the identification, classification and analysis of a large database of variants giving an insight into mechanisms generating them.
- Alexej Abyzov
- , Shantao Li
- & Mark B. Gerstein
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| Open AccessCheckpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements
Homologous recombination can overcome replication fork inactivation, but this can cause gross chromosomal rearrangements. Here, the authors show that DNA damage and intra-S phase checkpoints are blind to chromosome rearrangement in the first cell cycle, and are only induced in the second cell cycle.
- Saed Mohebi
- , Ken’Ichi Mizuno
- & Johanne M. Murray
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FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51
The F-box DNA helicase 1 (FBH1) is implicated in suppression of homologous recombination (HR), but the precise mechanism is unclear. Here, the authors show that FBH1 can ubiquitylate RAD51, a central player in HR, and controls the subcellular localization of RAD51.
- Wai Kit Chu
- , Miranda J. Payne
- & Ian D. Hickson
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Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions
Recombination intermediates must be resolved by mitosis to allow proper chromosome segregation. Here, the authors show that the structure-specific endonucleases Mus81-Msms4 and Yen1 are involved in the resolution of non-canonical Holliday junctions that would otherwise lead to anaphase bridges.
- Jonay García-Luis
- & Félix Machín
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TALEN and CRISPR/Cas9-mediated genome editing in the early-branching metazoan Nematostella vectensis
Genome editing has yet to be performed in non-bilaterian phyla. Here, Ikmi et al. develop techniques to use both TALEN and CRISPR/Cas9 in the sea anemone, Nematostella vectensis, and further leverage a locus expressing an endogenous fluorescent protein as a landing site for homologous recombination-mediated transgenesis.
- Aissam Ikmi
- , Sean A. McKinney
- & Matthew C. Gibson
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| Open AccessMicrohomology-mediated end-joining-dependent integration of donor DNA in cells and animals using TALENs and CRISPR/Cas9
One challenge facing the use of programmable nucleases in genome engineering is the requirement for homologous recombination. Here, Nakade et al.harness microhomology-mediated end-joining as a means of inserting exogenous coding sequences into the genome using both TALEN and CRISPR/Cas9 technologies.
- Shota Nakade
- , Takuya Tsubota
- & Ken-ichi T. Suzuki
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| Open AccessBRCA1 haploinsufficiency for replication stress suppression in primary cells
BRCA1 is a key breast and ovarian cancer suppressor involved in DSB repair. Here, the authors show that cells heterozygous for several BRCA1mutations are universally defective in the response to replication stress, which could contribute to the BRCA1 breast cancer development pathway.
- Shailja Pathania
- , Sangeeta Bade
- & David M. Livingston
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| Open AccessRNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells
A subset of cancers maintains telomere length independently of telomerase by activating alternative lengthening of telomeres (ALT) pathways. Here the authors show that RNaseH1 modulates telomeric homologous recombination frequencies in ALT cells by regulating the levels of RNA–DNA hybrids between TERRA and telomeric DNA.
- Rajika Arora
- , Yongwoo Lee
- & Claus M. Azzalin
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| Open AccessSpatial control of the GEN1 Holliday junction resolvase ensures genome stability
The human Holliday junction resolvase GEN1 functions during anaphase to eliminate recombination intermediates that block proper chromosome segregation. Here, the authors demonstrate that GEN1 activity is regulated independently of its phosphorylation status and relies on its active exclusion from the nucleus.
- Ying Wai Chan
- & Stephen C. West
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A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice
DNA double strand breaks are repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR) pathways. Here, Pai et al.discover that post-translational modification of lysine 36 of histone H3 plays a key role in determining double strand repair pathway choice.
- Chen-Chun Pai
- , Rachel S. Deegan
- & Timothy C. Humphrey
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Genome-wide transcriptome profiling of homologous recombination DNA repair
Defects in the homologous recombination repair of DNA can result in gene mutation and cancer. In this study, Peng et al.identify a gene signature associated with homologous recombination repair deficiency and show that this can be used both to predict repair defects and clinical outcome in cancer patients.
- Guang Peng
- , Curtis Chun-Jen Lin
- & Shiaw-Yih Lin
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Efficient genome engineering by targeted homologous recombination in mouse embryos using transcription activator-like effector nucleases
Genetically engineered mice are an important aspect of human disease research. Here, the authors use artificial transcription activator-like effector-nucleases to generate a mouse line with a conditionally targeted allele and suggest that this method can be easily adapted to any gene in the mouse genome.
- Daniel Sommer
- , Annika E. Peters
- & Marc Beyer
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DNA repair choice defines a common pathway for recruitment of chromatin regulators
Chromatin regulators facilitate repair of DNA double-strand breaks in chromosomal DNA. The authors show that the recruitment of such chromatin regulators to DNA lesions is controlled by the choice of DNA repair pathway.
- Gwendolyn Bennett
- , Manolis Papamichos-Chronakis
- & Craig L. Peterson
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A new protein complex promoting the assembly of Rad51 filaments
RecA/Rad51 proteins catalyse the recognition and exchange between two homologous DNA strands during homologous recombination. Sasanuma et al. now demonstrate that Rad51 association with ssDNA is mediated by a complex consisting of Psy3, Csm2, Shu1 and Shu2 proteins.
- Hiroyuki Sasanuma
- , Maki S. Tawaramoto
- & Akira Shinohara
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| Open AccessThe IncP-1 plasmid backbone adapts to different host bacterial species and evolves through homologous recombination
Plasmids are present in many bacteria and are often transferred between different species causing horizontal gene transfer. By comparing the sequences of 25 plasmid DNA backbones, the authors show that homologous recombination is prevalent in plasmids and that the plasmids have adapted to persist in different host bacteria.
- Peter Norberg
- , Maria Bergström
- & Malte Hermansson