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| Open AccessThe mechanism of replication stalling and recovery within repetitive DNA
DNA replication of repetitive sequences was recreated in a test tube using purified components. DNA alone was sufficient to induce stalling. Both stalling and recovery were dictated by the capacity of DNA to fold into unusual secondary structures.
- Corella S. Casas-Delucchi
- , Manuel Daza-Martin
- & Gideon Coster
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Article
| Open AccessA monomeric mycobacteriophage immunity repressor utilizes two domains to recognize an asymmetric DNA sequence
Bacteriophage repressor proteins downregulate viral lytic gene expression. Herein, the authors present the X-ray crystal structure of a monomeric repressor that binds an asymmetric DNA sequence using two independent domains.
- Reliza J. McGinnis
- , Chad A. Brambley
- & Jamie R. Wallen
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Article
| Open AccessSignal-processing and adaptive prototissue formation in metabolic DNA protocells
Signal processing for downstream functional and morphological adaptations is crucial for understanding and re-enacting features of living systems. Here, the authors show DNAzyme-containing, metabolic protocells that induce prototissue formation via chemical messenger communication due to in situ cleavage of upstream DNA signals.
- Avik Samanta
- , Maximilian Hörner
- & Andreas Walther
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Article
| Open AccessStructures of LIG1 that engage with mutagenic mismatches inserted by polβ in base excision repair
Ligase I seals two ends of DNA during DNA repair and replication. Here — solving structures of Ligase I with imperfect DNA harboring mismatches incorporated by DNA polymerase — the authors reveal how the repair proteins maintain fidelity at final ligation step.
- Qun Tang
- , Mitchell Gulkis
- & Melike Çağlayan
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Article
| Open AccessAnalysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining
Using X-ray crystallography and nonhomologous end-joining assays, this study reveals structural features within Polλ that provide it with the ability to bridge and stabilize tenuous DNA double-strand break ends, allowing for religation.
- Andrea M. Kaminski
- , Kishore K. Chiruvella
- & Lars C. Pedersen
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Article
| Open AccessSizing up DNA nanostructure assembly with native mass spectrometry and ion mobility
Interest in oligonucleotide nanostructures has recently surged in basic and applied research. Here, the authors use native mass spectrometry and ion mobility to elucidate a prototypical hexameric DNA barrel structure as well as intermediates and byproducts of the assembly reaction.
- Jeroen F. van Dyck
- , Jonathan R. Burns
- & Frank Sobott
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Article
| Open AccessStructural basis for MTA1c-mediated DNA N6-adenine methylation
DNA N6-adenine methylation (6 mA) plays a crucial role in epigenetic regulation in eukaryotes. Here, the authors determined nine crystal structures of the ciliates 6 mA methyltransferase complexes, providing the molecular basis for understanding the functions of 6 mA.
- Jiyun Chen
- , Rong Hu
- & Liang Liu
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Article
| Open AccessThe influence of Holliday junction sequence and dynamics on DNA crystal self-assembly
Engineered crystal architectures from DNA have become a foundational goal for nanotechnological precise arrangement. Here, the authors systematically investigate the structures of 36 immobile Holliday junction sequences and identify the features allowing the crystallisation of most of them, while 6 are considered fatal.
- Chad R. Simmons
- , Tara MacCulloch
- & Hao Yan
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Article
| Open AccessMechanism of nucleotide discrimination by the translesion synthesis polymerase Rev1
Rev1 is a specialized translesion synthesis DNA polymerase involved in the bypass DNA damage during DNA replication. Here, the authors determine the structural basis for preferential incorporation of dCTP by Rev1 during bypass of DNA damage.
- Tyler M. Weaver
- , Timothy H. Click
- & Bret D. Freudenthal
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Article
| Open AccessA reversibly gated protein-transporting membrane channel made of DNA
Artificial systems to control the transport of molecules across biomembranes can be useful for biosensing or drug delivery. Here, the authors assemble a DNA channel enabling the precisely timed, stimulus-controlled transport of functional proteins across bilayer membranes.
- Swarup Dey
- , Adam Dorey
- & Hao Yan
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Article
| Open AccessDifferences in RNA polymerase II complexes and their interactions with surrounding chromatin on human and cytomegalovirus genomes
Here the authors digested chromatin with DNA fragmentation factor (DFF) prior to chromatin immunoprecipitation (DFF-ChIP) to depict transcription complex interactions with neighboring nucleosomes in cells. Applying this method to human cytomegalovirus (HMCV)-infected cells, they find that the viral genome is underchromatinized, leading to fewer transcription complex interactions with nucleosomes.
- Benjamin M. Spector
- , Mrutyunjaya Parida
- & David H. Price
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Article
| Open AccessProgrammable design of isothermal nucleic acid diagnostic assays through abstraction-based models
Detecting nucleic acids often requires choosing between different amplification mechanisms. Here the authors present a generalisable and programmable isothermal methodology, demonstrated in clinical applications, including for multiplexed detection of short miRNAs.
- Gaolian Xu
- , Julien Reboud
- & Jonathan M. Cooper
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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 AccessMyosin VI regulates the spatial organisation of mammalian transcription initiation
The actin-based molecular motors, myosins, have also been linked to transcription, but their precise role has remained elusive. Here the authors show RNA polymerase II (RNAPII) is lost from chromatin upon myosin perturbation and that myosin acts as a molecular anchor to maintain RNAPII spatial organisation.
- Yukti Hari-Gupta
- , Natalia Fili
- & Christopher P. Toseland
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Article
| Open AccessMutation-specific reporter for optimization and enrichment of prime editing
While prime editing is a promising technique, some genomic sites remain difficult to edit. Here the authors present fluoPEER, fluorescent prime editing and enrichment reporter, to rank the efficiency of pegRNAs and prime editor variants.
- I. F. Schene
- , I. P. Joore
- & S. A. Fuchs
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Article
| Open AccessA mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6
Cryo-EM structures of S. cerevisiae ORC bound to DNA and Cdc6 reveal an autoinhibited conformation and suggest a mechanism of origin licensing control in response to CDK phosphorylation.
- Jan Marten Schmidt
- , Ran Yang
- & Franziska Bleichert
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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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Review Article
| Open AccessSynthetic DNA applications in information technology
Synthetic DNA is the basis for promising technologies in data storage, barcoding, computing 62 and sercurity. In this review, the authors provide an overview of the field and its future.
- Linda C. Meiser
- , Bichlien H. Nguyen
- & Robert N. Grass
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Article
| Open AccessChirality transmission in macromolecular domains
Chiral communication can propagate in secondary structures within the effective intermolecular force (IMF) range but it is not known whether long-range chiral communication exists between tertiary peptide structures. Here, the authors use single-molecule force spectroscopy to investigate chiral interaction between DNA duplexes/triplexes and peptide coiled-coils and demonstrate chiral communication beyond the IMF distance.
- Shankar Pandey
- , Shankar Mandal
- & Hanbin Mao
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Article
| Open AccessG-quadruplex DNA structures in human stem cells and differentiation
Whether G-quadruplexes (G4s) regulate stem cell self-renewal and fate determination during embryonic development is not well understood. Here, the authors reveal that the embryonic stem cell state is defined by very high G4 abundance. G4s are progressively lost during differentiation as cells transit to lower lineage potential while artificial G4 stabilisation leads to delayed differentiation.
- Katherine G. Zyner
- , Angela Simeone
- & Shankar Balasubramanian
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Article
| Open AccessThe biogenesis and function of nucleosome arrays
Nucleosomes form arrays with even spacing between them in virtually all eukaryotes; however, their biogenesis is incompletely understood. Here the authors show that nucleosome density and DNA sequence along with the Ino80 chromatin remodeling complex play a role in nucleosome array formation in yeast and that the transcriptional machinery disrupts evenly-spaced nucleosomes.
- Ashish Kumar Singh
- , Tamás Schauer
- & Felix Mueller-Planitz
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Article
| Open AccessStructural basis of Ty3 retrotransposon integration at RNA Polymerase III-transcribed genes
Ty3 retrotransposon integrates with an exquisite specificity upstream of RNA Polymerase III-transcribed genes, such as transfer RNAs. Here the authors resolve a cryo-EM structure of an active Ty3 intasome in complex with a TFIIIB-bound tRNA promoter, shedding light into the molecular determinants of harmless retrotransposition.
- Guillermo Abascal-Palacios
- , Laura Jochem
- & Alessandro Vannini
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Article
| Open AccessAcyl carrier protein promotes MukBEF action in Escherichia coli chromosome organization-segregation
E. coli MukBEF is an SMC complex that plays key roles in chromosome organization-segregation. Here the authors show that the interaction between MukBEF and the Acyl Carrier Protein (AcpP) is essential for MukBEF activity in vitro (ATPase) and in vivo.
- Josh P. Prince
- , Jani R. Bolla
- & David J. Sherratt
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Article
| Open AccessAptamer-assisted tumor localization of bacteria for enhanced biotherapy
Bacteria-based therapy has shown promise for cancer treatment. To enhance tumor accumulation, here the authors describe the design of tumor specific aptamer-conjugated bacteria, to improve intratumor localization and enhance therapeutic efficacy.
- Zhongmin Geng
- , Zhenping Cao
- & Weihong Tan
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Article
| Open AccessDistinct RPA domains promote recruitment and the helicase-nuclease activities of Dna2
An enzymatic ensemble including Dna2 functions in DNA end resection; the function of the single-stranded DNA binding protein RPA in this complex has been underappreciated. Here the authors employ molecular modeling, biochemistry, and single molecule biophysics to reveal RPA directly promotes Dna2 recruitment, nuclease and helicase activities.
- Ananya Acharya
- , Kristina Kasaciunaite
- & Petr Cejka
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Article
| Open AccessCryo-EM structure of human Pol κ bound to DNA and mono-ubiquitylated PCNA
Translesion Synthesis is a process that enables cells to overcome the deleterious effects of replication stalling caused by DNA lesions. Here the authors present a Cryo-EM structure of human Y-family DNA polymerase k (Pol k) bound to PCNA, P/T DNA and an incoming nucleotide; and propose a model for polymerase switching in which “carrier state” Pol k is recruited to PCNA.
- Claudia Lancey
- , Muhammad Tehseen
- & Alfredo De Biasio
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Article
| Open AccessSingle-molecule junction spontaneously restored by DNA zipper
The versatility of DNA has inspired many single-molecule investigations utilizing nanotechnology. Harashima et al. have a somewhat different take on the subject and study a zipper configuration bridging electrodes that resembles an active electro-mechanical component instead.
- Takanori Harashima
- , Shintaro Fujii
- & Tomoaki Nishino
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Article
| Open AccessSupercoiling and looping promote DNA base accessibility and coordination among distant sites
DNA supercoiling can result in underwinding with negative supercoiling or overwinding with positive supercoiling of the DNA double helix. Here the authors reveal insights into the dynamic relationship between DNA supercoiling-induced sequence-dependent disruptions to base pairing, DNA looping, and the shape of the DNA molecule.
- Jonathan M. Fogg
- , Allison K. Judge
- & Lynn Zechiedrich
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Article
| Open AccessRad27 and Exo1 function in different excision pathways for mismatch repair in Saccharomyces cerevisiae
Defects in DNA mismatch repair (MMR) have been linked to inherited and sporadic cancers. Here the authors demonstrate that the DNA repair protein Rad27 (human FEN1) functions in one of three redundant mispair excision pathways, where its flap endonuclease activity catalyzes mispair excision.
- Felipe A. Calil
- , Bin-Zhong Li
- & Richard D. Kolodner
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Article
| Open AccessA CDK-regulated chromatin segregase promoting chromosome replication
How cells coordinate chromatin dynamics with the cell cycle machinery to promote genome duplication during S phase is still a matter of study. Here the authors reveal by in vitro reconstitution assays that the AAA + -ATPase containing Yta7 protein in S. cerevisiae promotes chromatin.
- Erika Chacin
- , Priyanka Bansal
- & Christoph F. Kurat
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Article
| Open AccessAutonomous DNA nanostructures instructed by hierarchically concatenated chemical reaction networks
Integration and communication of distinct chemical reaction networks is a biological strategy for controlling dynamics of hierarchical structures. Here, the authors report ATP-fuelled autonomous DNA nanotube assembly regulated by DNA strand displacement reactions, which are induced and controlled by an upstream enzyme reaction network of concurrent ATP-mediated ligation and restriction of DNA components.
- Jie Deng
- & Andreas Walther
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Article
| Open AccessA last-in first-out stack data structure implemented in DNA
DNA is becoming increasingly used as a medium to store non-genetic information. Here the authors present a dynamic stack data structure implemented as a DNA polymer chemistry able to record and retrieve signals in a last-in first-out order.
- Annunziata Lopiccolo
- , Ben Shirt-Ediss
- & Natalio Krasnogor
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Article
| Open AccessA deep learning model for predicting next-generation sequencing depth from DNA sequence
DNA probes used in next generation sequencing (NGS) have variable hybridisation kinetics, resulting in non-uniform coverage. Here, the authors develop a deep learning model to predict NGS depth using DNA probe sequences and apply to human and non-human sequencing panels.
- Jinny X. Zhang
- , Boyan Yordanov
- & David Yu Zhang
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Article
| Open AccessTissue-specific 5-hydroxymethylcytosine landscape of the human genome
Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues and found 5hmC shows tissue-specific patterns.
- Bo He
- , Chao Zhang
- & Chengqi Yi
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Article
| Open AccessPromoter G-quadruplexes and transcription factors cooperate to shape the cell type-specific transcriptome
G-quadruplex (G4) structures play complex roles linked to transcription regulation. Here the authors, by comparing G4 location and transcript levels in liposarcoma and keratinocyte cells, reveal that G4s cooperate with transcription factors to determine cell-specific transcriptional programs.
- Sara Lago
- , Matteo Nadai
- & Sara N. Richter
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Article
| Open AccessThe structure of ORC–Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6
Eukaryotic DNA replication is mediated by many proteins which are tightly regulated for an efficient firing of replication at each cell cycle. Here the authors report a cryo-EM structure of the yeast ORC–Cdc6 bound to an 85-bp ARS1 origin DNA revealing additional insights into how Cdc6 contributes to origin DNA recognition.
- Xiang Feng
- , Yasunori Noguchi
- & Huilin Li
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Article
| Open AccessCRISPR-Associated Primase-Polymerases are implicated in prokaryotic CRISPR-Cas adaptation
CAPPs are putative Primase-Polymerases associated with CRISPR-Cas operons. Here, the authors show CAPPs genetic and physical association with Cas1 and Cas2, their capacity to function as DNA-dependent DNA primases and DNA polymerases, and that Cas1-Cas2 complex adjacent to CAPP has bona fide spacer integration activity.
- Katerina Zabrady
- , Matej Zabrady
- & Aidan J. Doherty
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Comment
| Open AccessHoming in on genomic instability as a therapeutic target in cancer
While genomic instability is a hallmark of cancer, its genetic vulnerabilities remain poorly understood. Identifying strategies that exploit genomic instability to selectively target cancer cells is a central challenge in cancer biology with major implications for anti-cancer drug development.
- Craig M. Bielski
- & Barry S. Taylor
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Article
| Open AccessRuler elements in chromatin remodelers set nucleosome array spacing and phasing
Although chromatin remodelers have been shown to align nucleosome arrays to barriers and to generate spacing regularity among nucleosomes within arrays, it has remained unclear how the distance to barrier and the spacing length are determined in absolute terms. Here, the authors reveal that remodelers contain a ‘ruler’ element that sets remodeler-specific alignment and spacing distances when generating nucleosome arrays.
- Elisa Oberbeckmann
- , Vanessa Niebauer
- & Philipp Korber
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Article
| Open AccessGuiding functions of the C-terminal domain of topoisomerase IIα advance mitotic chromosome assembly
Topoisomerase IIα (topo IIα) is critical for mitotic chromatid assembly. Here the authors report a refinement of the mitotic chromatid reconstitution assay and provide novel insights into the C-terminal domain (CTD) of topo IIα.
- Keishi Shintomi
- & Tatsuya Hirano
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Article
| Open AccessOn-demand synthesis of phosphoramidites
The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers.
- Alexander F. Sandahl
- , Thuy J. D. Nguyen
- & Kurt V. Gothelf
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Article
| Open AccessN-aryl pyrido cyanine derivatives are nuclear and organelle DNA markers for two-photon and super-resolution imaging
It is challenging to develop DNA probes that allow staining of both organelle and nuclear DNA, are compatible with super resolution imaging and avoid UV-light photo-excitation. The authors overcome these issues with N-aryl pyrido cyanine derivatives showing high DNA specificity and membrane permeability.
- Kakishi Uno
- , Nagisa Sugimoto
- & Yoshikatsu Sato
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Article
| Open AccessMachine learning guided aptamer refinement and discovery
Current aptamer discovery approaches are unable to probe the complete space of possible sequences. Here, the authors use machine learning to facilitate the development of DNA aptamers with improved binding affinities, and truncate them without significantly compromising binding affinity.
- Ali Bashir
- , Qin Yang
- & B. Scott Ferguson
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Article
| Open AccessMechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism
The GntR superfamily is one of the largest families of transcription factors in prokaryotes. Here the authors combine biophysical analysis and structural biology to dissect the mechanism by which NanR — a GntR-family regulator — binds to its promoter to repress the transcription of genes necessary for sialic acid metabolism.
- Christopher R. Horne
- , Hariprasad Venugopal
- & Renwick C. J. Dobson
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Article
| Open AccessDNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine
7,8-dihydro-8-oxoguanine and 7,8-dihydro-8-oxoadenine (oxoA) are generated upon oxidative damage to DNA, but the biological effects of oxoA are not well known. Here, the authors report that only oxoA forms DNA interstrand crosslinks (ICLs) upon secondary oxidation and that these ICLs can be induced by reactive halogen species, one-electron oxidants and the myeloperoxidase/H2O2/Cl- system.
- Aaron L. Rozelle
- , Young Cheun
- & Seongmin Lee
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Article
| Open AccessProgrammable site-selective labeling of oligonucleotides based on carbene catalysis
The methods for investigation of DNA-binding proteins require site-selective chemical modifications to be introduced into oligonucleotides. Here, the authors report a chemo- and regioselective method for the modification of unpaired guanosines in single- and double-stranded oligonucleotides, based on Rh(I)-carbene catalysis.
- Yang-Ha Lee
- , Eunsoo Yu
- & Cheol-Min Park
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Article
| Open AccessAn extended APOBEC3A mutation signature in cancer
The APOBEC mutation signature contributes to a significant percentage of human cancers. Here the authors via biochemical and computational analyses shed light on how DNA primary sequence and secondary structure jointly influence A3A substrate optimality.
- Adam Langenbucher
- , Danae Bowen
- & Michael S. Lawrence
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Article
| Open AccessNonenzymatic polymerase-like template-directed synthesis of acyclic l-threoninol nucleic acid
A world preceding the prebiotic RNA-world may have been based on xeno nucleic acids (XNAs), but their replication likely did not require enzymes. Here, the authors demonstrate template-directed non-enzymatic synthesis of an XNA, acyclic l-threoninol nucleic acid, via chemical ligation mediated by N-cyanoimidazole, and achieve a pseudo-primer extension of this XNA with all four nucleobases.
- Keiji Murayama
- , Hikari Okita
- & Hiroyuki Asanuma
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Article
| Open AccessMolecular mechanism for vitamin C-derived C5-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1
C5-glyceryl-methylcytosine is a DNA modification that plays a role in the regulation of green alga photosynthesis and is catalysed by CMD1, using vitamin C (VC) as a co-substrate. Here, the authors provide insights into the catalytic mechanism of CMD1 by determining the crystal structures of apo CMD1 and CMD1 bound to either VC or DNA, as well as the ternary CMD1/VC/DNA complex structure.
- Wenjing Li
- , Tianlong Zhang
- & Jianping Ding