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3D genome organization contributes to genome instability at fragile sites
Common fragile sites are regions susceptible to replication stress and are prone to chromosomal instability. Here, the authors, by analyzing the contribution of 3D chromatin organization, identify and characterize a fragility signature and precisely map these fragility regions.
- Dan Sarni
- , Takayo Sasaki
- & Batsheva Kerem
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Specificity 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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Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
The ATM kinase is a key regulator of the DNA damage response to double-strand breaks (DSBs) and its homozygous loss in patients predisposes to lymphoid malignancies. Here, the authors develop a Tdp2−/− Atm−/− double-deficient mouse model to uncover topoisomerase II-induced DSBs as significant drivers of the genomic rearrangements that underpin these tumours.
- Alejandro Álvarez-Quilón
- , José Terrón-Bautista
- & Felipe Cortés-Ledesma
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Rad50 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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PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
The poly(ADP-ribose) polymerases play a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. Here the authors characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks.
- Deepti Sharma
- , Louis De Falco
- & Curt A. Davey
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Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
- Julio Aguado
- , Agustin Sola-Carvajal
- & Fabrizio d’Adda di Fagagna
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A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome
Topoisomerase 2 (Top2) is known to resolve DNA topological stress through double strand breaks (DSBs), yet Top2 inhibition has been reported to result in a significant amount of single-strand breaks (SSBs). Here the authors develop CC-seq—a method that allows direct mapping of both Top2-linked SSBs and DSBs—and reveal a significant impact of primary DNA sequence on Top2 directed cleavage.
- William H. Gittens
- , Dominic J. Johnson
- & Matthew J. Neale
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Molecular basis of microhomology-mediated end-joining by purified full-length Polθ
DNA polymerase θ is a polymerase-helicase essential for microhomology-mediated end-joining (MMEJ) or alternative end-joining of DNA. Here the authors use biochemical and biophysical methods to reveal how full-length human DNA polymerase θ performs MMEJ at the molecular level.
- Samuel J. Black
- , Ahmet Y. Ozdemir
- & Richard T. Pomerantz
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Genetic determinants of cellular addiction to DNA polymerase theta
Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.
- Wanjuan Feng
- , Dennis A. Simpson
- & Gaorav P. Gupta
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A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1
Regulation of post translational modification of 53BP1 is critical for genome integrity and regulation of DNA damage response. Here the authors reveal a CDK5-PP4 phospho-signaling cascade that leads 53BP1 to sites of DNA damage.
- Xiao-Feng Zheng
- , Sanket S. Acharya
- & Dipanjan Chowdhury
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Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.
- Jian-Fang Ning
- , Monica Stanciu
- & Samuel D. Rabkin
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Structure and function of the Orc1 BAH-nucleosome complex
The Origin Recognition Complex (ORC) plays conserved and diverse roles in eukaryotes. Here the authors present the structure of a chromatin interacting domain of yeast Orc1 in complex with the nucleosome core particle, revealing that Orc1 interacts with the histone H4 tail irrespective of K16 acetylation; a modification that regulates accessibility to chromatin.
- Pablo De Ioannes
- , Victor A. Leon
- & Karim-Jean Armache
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qDSB-Seq is a general method for genome-wide quantification of DNA double-strand breaks using sequencing
Measuring relative frequencies of DNA double-strand breaks between loci does not provide the full physiological relevance of those breaks. Here Rowicka and colleagues present qDSB-Seq method which uses spike-in double-strand breaks induced by a restriction enzyme to accurately quantify DNA damage.
- Yingjie Zhu
- , Anna Biernacka
- & Maga Rowicka
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Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks
Occurrence of DNA double-strand break (DSB) repair is important for genome integrity. Here, the authors reveal that Pellino1 is a DSB-responsive ubiquitin ligase required for promoting the accumulation of ATM and MRN complex at DSB sites via NBS1 ubiquitination.
- Geun-Hyoung Ha
- , Jae-Hoon Ji
- & Chang-Woo Lee
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Human 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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Quantitative sensing and signalling of single-stranded DNA during the DNA damage response
DNA damage triggers checkpoint signalling mechanisms. Here the authors reveal differential phosphorylation of targets of the Mec1-Ddc2 checkpoint kinase by analyzing the effect of quantitatively different ssDNA signals.
- Susanne C. S. Bantele
- , Michael Lisby
- & Boris Pfander
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A 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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The 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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Shu 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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ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB
Transcription-coupled homologous recombination (TC-HR) is activated by reactive oxygen species-induced DNA damage to maintain transcribed genome stability. The authors demonstrate that R loops are induced by ROS at the transcribed genome, triggering a CSB-RAD52- dependent but BRCA1/2-independent RAD51 loading for repair.
- Yaqun Teng
- , Tribhuwan Yadav
- & Li Lan
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Regulatory control of DNA end resection by Sae2 phosphorylation
It has previously been established that DNA end resection in yeast and in humans is under CDK control. Here the authors explain how phosphorylation regulates the capacity of Sae2 — the yeast orthologue of human CtIP — to promote DNA end resection.
- Elda Cannavo
- , Dominic Johnson
- & Petr Cejka
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An OB-fold complex controls the repair pathways for DNA double-strand breaks
How repair pathway selection occurs is still a matter of debate and many factors have been associated to this function. Here the authors provide insight into the role of FAM35A and C20ORF196, two REV7-interacting proteins, which are recruited at double-strand breaks to promote non-homologous end joining repair.
- Shengxian Gao
- , Sumin Feng
- & Dongyi Xu
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Spatiotemporal 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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PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair
PAXX functions as part of the nonhomologous end-joining pathway to repair double-strand DNA breaks. Here the authors show PAXX and its paralogs interact with polymerase lambda to promote joining of incompatible ends.
- Andrew Craxton
- , Deeksha Munnur
- & Michal Malewicz
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The concerted roles of FANCM and Rad52 in the protection of common fragile sites
Fanconi anemia core proteins have been linked to common fragile site stability. Here the authors shed light into the role of FANCM in common fragile site protection by suppressing double-strand break formation and mitotic recombination.
- Hailong Wang
- , Shibo Li
- & Xiaohua Wu
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ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
Following double-strand break a cascade of events leads to the recruitment of repair factors to damaged sites. Here the authors identify ZNF506 as a key factor that mediates post-translational modification changes in H2AX affecting the DNA damage response.
- Somaira Nowsheen
- , Khaled Aziz
- & Zhenkun Lou
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SUMO2 conjugation of PCNA facilitates chromatin remodeling to resolve transcription-replication conflicts
Transcription-replication conflicts need to be resolved to minimize genome instability. Here the authors show that SUMO2-conjugated PCNA destabilizes RNAPII from chromatin, enhances replication progression and limits transcription-induced DNA damage at common fragile sites.
- Min Li
- , Xiaohua Xu
- & Yilun Liu
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Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR
Tudor interacting repair regulator (TIRR) is a negative regulator of 53BP1 in DNA damage repair processes. Here the authors give mechanistic insights into how TIRR mediates suppression by solving the crystal structure of TIRR bound to the 53BP1 tandem Tudor domain (TTD).
- Jiaxu Wang
- , Zenglin Yuan
- & Xiuhua Liu
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miR-103 promotes endothelial maladaptation by targeting lncWDR59
MicroRNAs play important roles in endothelial cells injury, proliferation and maladaptation by negatively regulating posttranscriptional gene expression. Here the authors uncover the role of the long non coding RNA lncWDR59, target of miR-103, in endothelial maladaptation.
- Lucia Natarelli
- , Claudia Geißler
- & Andreas Schober
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C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains
Many factors are involved in end joining (EJ) repair of double strand breaks. Here the authors present a method to identify a chromosomal break repair event that requires classical non homologues end joining (C-NHEJ) using Cas9-based end joining tools, and define a role of CNHEJ factor XLF in repair.
- Ragini Bhargava
- , Manbir Sandhu
- & Jeremy M. Stark
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Article
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Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR
The p53-binding protein 1 (53BP1) regulates the choice of the DNA double-strand break repair pathway. Here the authors present the crystal structure of Tudor-interacting repair regulator (TIRR) bound to the 53BP1 tandem Tudor domain, which reveals how TIRR blocks H4K20me2 binding to 53BP1 Tudor and functionally differs from its paralog Nudt16.
- Yaxin Dai
- , Aili Zhang
- & Zheng Zhou
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GFI1 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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MRN 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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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1
Mutations in BRCA1 are associated with an increased risk of breast and ovarian cancer. Here the authors show that EDC4, a component of P-bodies, is a member of the BRCA1 complex with roles in stimulating end resection at breaks.
- Gonzalo Hernández
- , María José Ramírez
- & Jordi Surrallés
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Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations
Recent studies suggest key roles of RNA in DNA double-strand breaks repair. Here the authors identify the helicase senataxin to be involved in DNA repair and resolve RNA:DNA hybrids forming at DNA double-strand breaks.
- Sarah Cohen
- , Nadine Puget
- & Gaëlle Legube
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ATM 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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BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability
The genomic instability phenotype characteristic of BRCA2-deficient cells is not fully mechanistically understood. Here the authors show BRCA2 inactivation destabilizes RPA-coated single-stranded DNA and leads to toxic non homologous end-joining events.
- Jinhua Han
- , Chunyan Ruan
- & Jun Huang
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Article
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AUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway
DNA double strand breaks can be repaired by homology-independent or homology-directed mechanisms. The choice between these pathways is a key event for genomic stability maintenance. Here the authors identify and characterize AUNIP, as a factor involved in tilting the balance towards homology repair.
- Jiangman Lou
- , Hongxia Chen
- & Jun Huang
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Article
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ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability
MDC1 is a key component of the DNA damage response and interacts with several factors such as γ-H2AX. Here the authors show that MDC1 interacts with ID3, facilitating MDC1 recruitment to sites of damage and repair of breaks.
- Jung-Hee Lee
- , Seon-Joo Park
- & Ho Jin You
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Article
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DNA 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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Article
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The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites
The choice between homologous recombination and non-homologous end-joining is largely influenced by cell cycle. Here the authors show that APCCdh1 promotes homologous recombination by removing USP1, allowing polyubiquitinated histones to recruit BRCA1.
- Kyungsoo Ha
- , Chengxian Ma
- & Pumin Zhang
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Article
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USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response
RAP80 helps to recruit BRCA1 to double-strand breaks, facilitating DNA damage responses. Here the authors report that phosphorylated USP13 deubiquitinates RAP80 after DNA damage, prompting recruitment to the break site.
- Yunhui Li
- , Kuntian Luo
- & Jian Yuan
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A damaged genome’s transcriptional landscape through multilayered expression profiling around in situ-mapped DNA double-strand breaks
DNA double strand breaks (DSBs) are among the most deleterious types of damage and there is strong evidence indicating a relationship between breaks and transcription. Here the authors provide a high-resolution, genome-wide map of induced DSBs and observe ATM-dependent transcriptional repression.
- Fabio Iannelli
- , Alessandro Galbiati
- & Fabrizio d’Adda di Fagagna
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BLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks
Double-strand breaks are a major DNA lesion that can occur by endogenous and exogenous processes. Here the authors present BLISS—Breaks LabellingIn Situand Sequencing—to map breaks across the genome.
- Winston X. Yan
- , Reza Mirzazadeh
- & Nicola Crosetto
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Article
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PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA
Chromosomal rearrangements are key events in the pathogenesis of a range of disorders. Here the authors utilize a zinc finger nuclease translocation reporter to identify PARP3 as a regulator of these events at sites enriched for G quadruplex DNA.
- Tovah A. Day
- , Jacob V. Layer
- & David M. Weinstock
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Management of E. coli sister chromatid cohesion in response to genotoxic stress
Homologous recombination of DNA lesions in bacteria involves sister chromatid pairing. Here, the authors show that RecN promotes contacts between sister chromatids and facilitates repair.
- Elise Vickridge
- , Charlene Planchenault
- & Olivier Espéli
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Article
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Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids
ICF syndrome cells exhibit shortened telomeres and elevated levels of the noncoding RNA TERRA. Here the authors show this is associated with high levels of DNA damage, suggesting an increase in telomere dysfunction due to the formation of DNA: RNA hybrids
- Shira Sagie
- , Shir Toubiana
- & Sara Selig
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Article
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Characterization of the interplay between DNA repair and CRISPR/Cas9-induced DNA lesions at an endogenous locus
CRISPR-Cas9 has rapidly become a common molecular biology tool for modifying genomes and has been modified to generate single-strand nicks as well as double-strand breaks. Here the authors explore the DNA repair pathways activated by the different variants of Cas9.
- Anne Bothmer
- , Tanushree Phadke
- & Cecilia Cotta-Ramusino
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Profiling DNA damage response following mitotic perturbations
DNA damage arising from replication stress is well studied, but the effect of mitotic errors on genome integrity is less understood. Here the authors knock down 47 mitotic regulators and record how they impact on DNA breakage events, providing a resource for future studies on the relation between cell division and genome integrity.
- Ronni S. Pedersen
- , Gopal Karemore
- & Claudia Lukas
Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ