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| Open AccessReconstitution of a telomeric replicon organized by CST
The Polα–primase-associated CST complex organizes telomeric C-strand DNA synthesis, and, in combination with telomerase, it carries out complete replication of the single-stranded DNA overhang found at human telomeres.
- Arthur J. Zaug
- , Karen J. Goodrich
- & Thomas R. Cech
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Structures of the human CST-Polα–primase complex bound to telomere templates
A structural analysis demonstrates how the single-stranded DNA-binding accessory protein complex CST physically organizes the human DNA polymerase-α–primase complex for efficient primer synthesis during telomere replication.
- Qixiang He
- , Xiuhua Lin
- & Ci Ji Lim
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Article |
Structure of Tetrahymena telomerase-bound CST with polymerase α-primase
Cryo-electron microscopy structures of Tetrahymena thermophila telomerase-bound Ctc1–Stn1–Ten1 and DNA polymerase α–primase provide insights into the molecular mechanisms underlying telomere replication and maintenance.
- Yao He
- , He Song
- & Juli Feigon
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Article
| Open AccessGTSF1 accelerates target RNA cleavage by PIWI-clade Argonaute proteins
The evolutionarily conserved RNA-binding protein GTSF1 and its homologues interact with members of the PIWI class of Argonaute proteins, increasing the efficiency of the RNA-cleaving activity of PIWI proteins, an essential function across the animal kingdom.
- Amena Arif
- , Shannon Bailey
- & Phillip D. Zamore
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Article
| Open AccessStructural insights into dsRNA processing by Drosophila Dicer-2–Loqs-PD
Structures of the Dcr-2–Loqs-PD complex while it is processing a double-stranded RNA (dsRNA) substrate elucidate the interactions between Dcr-2 and Loqs-PD, and show that Dcr-2 undergoes substantial conformational changes during a dsRNA-processing cycle.
- Shichen Su
- , Jia Wang
- & Jinbiao Ma
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Article
| Open AccessStructure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex
Cryo-electron microscopy structures of Drosophila Dicer-2–R2D2 complexes with and without small interfering RNA reveal how the RNA is presented to Argonaute in the correct orientation for viral gene silencing.
- Sonomi Yamaguchi
- , Masahiro Naganuma
- & Osamu Nureki
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Article |
Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy
- Mark Chaffin
- , Irinna Papangeli
- & Patrick T. Ellinor
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Article |
eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining
Single-molecule spectroscopy and structural studies were used to examine the dynamics of association of eIF1A and eIF5B with the human translation initiation complex and their role in presenting tRNA to the complex to initiate translation.
- Christopher P. Lapointe
- , Rosslyn Grosely
- & Joseph D. Puglisi
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Article |
cBAF complex components and MYC cooperate early in CD8+ T cell fate
cBAF is a negative determinant of memory T cell fate and the manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.
- Ao Guo
- , Hongling Huang
- & Douglas R. Green
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Article |
Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy
Treatment with neoadjuvant BRAF/MEK-targeted therapy results in higher rates of major pathological response in female compared with male patients with melanoma, and pharmacological inhibition of androgen receptor signalling improved the responses of male and female mice to BRAF/MEK-targeted therapy.
- Christopher P. Vellano
- , Michael G. White
- & Jennifer A. Wargo
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Article
| Open AccessMechanism of replication origin melting nucleated by CMG helicase assembly
Cryo-electron microscopy structures of the sequential assembly of the CMG replicative helicase on a chromatinized origin of replication provide insights into the mechanism through which DNA melting is initiated by ATP binding.
- Jacob S. Lewis
- , Marta H. Gross
- & Alessandro Costa
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Matters Arising |
Limitations of gamete sequencing for crossover analysis
- Carl Veller
- , Shunxin Wang
- & Nancy Kleckner
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Research Briefing |
A hybrid control model for the eukaryotic cell cycle
The organizational principles of the eukaryotic cell cycle have yet to be pinned down, and two opposing models have been put forward. Genetic and proteomics analyses in a model eukaryote, fission yeast, reveal that the cell cycle is organized through a hybrid of both models, although the contribution of one strongly outweighs the other.
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| Open AccessCohesin-mediated loop anchors confine the locations of human replication origins
A study shows that the three-dimensional conformation of the human genome influences the positioning of DNA replication initiation zones, highlighting cohesin-mediated loop anchors as essential determinants of their precise location.
- Daniel J. Emerson
- , Peiyao A. Zhao
- & Jennifer E. Phillips-Cremins
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| Open AccessMechanism of mitoribosomal small subunit biogenesis and preinitiation
Structural analysis of several small mitoribosomal subunit intermediates reveals a sequential mechanism of biogenesis, and how assembly links to initiation to form active mitoribosomes.
- Yuzuru Itoh
- , Anas Khawaja
- & Alexey Amunts
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Differential cofactor dependencies define distinct types of human enhancers
The systematic categorization of human enhancers by their cofactor dependencies provides a conceptual framework to understand the sequence and chromatin diversity of enhancers and their roles in different gene-regulatory programmes.
- Christoph Neumayr
- , Vanja Haberle
- & Alexander Stark
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Article
| Open AccessIsland-specific evolution of a sex-primed autosome in a sexual planarian
Assembly and analysis of the Schmidtea mediterranea genome indicate that this planarian’s chromosome 1 may be evolving into a sex chromosome.
- Longhua Guo
- , Joshua S. Bloom
- & Leonid Kruglyak
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Compatibility rules of human enhancer and promoter sequences
A new high-throughput assay applied to 1,000 enhancers and 1,000 promoters in human cells reveals how different classes of enhancers and promoters control RNA expression.
- Drew T. Bergman
- , Thouis R. Jones
- & Jesse M. Engreitz
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Fast and efficient DNA replication with purified human proteins
A biochemical reconstitution of human replisomes that provides a system for future studies of DNA metabolic processes.
- Yasemin Baris
- , Martin R. G. Taylor
- & Joseph T. P. Yeeles
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Gibbin mesodermal regulation patterns epithelial development
Characterization of Gibbin, encoded by AHDC1, offers insights into the epidermal and mesodermal patterning phenotypes seen in Xia–Gibbs and related syndromes in humans, which derive from abnormal mesoderm maturation as a result of gene-specific DNA methylation decisions.
- Ann Collier
- , Angela Liu
- & Anthony E. Oro
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Article
| Open AccessMCM complexes are barriers that restrict cohesin-mediated loop extrusion
Single-nucleus Hi-C of embryos, polymer simulations and single-molecule imaging collectively reveal that MCM complexes influence genome folding and gene expression by impeding DNA loop extrusion.
- Bart J. H. Dequeker
- , Matthias J. Scherr
- & Kikuë Tachibana
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Article |
Intracellular lipid surveillance by small G protein geranylgeranylation
In Caenorhabditis elegans, geranylgeranyl conjugation to RAB-11.1 acts as a lipid sensor to regulate nutrient uptake and lipid metabolism in response to metabolic demand.
- Abigail Watterson
- , Lexus Tatge
- & Peter M. Douglas
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News |
Origin of life theory involving RNA–protein hybrid gets new support
Structure that links amino acids suggests that early organisms could have been based on an RNA–protein mix.
- Davide Castelvecchi
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Research Briefing |
The initiation of DNA synthesis in molecular detail
Life on Earth depends on the ability of cells to duplicate their genetic material, encoded in DNA molecules, and pass this information on to the next generation. Elucidation of the molecular mechanism underlying the priming step of this copying process provides insights into how DNA replication begins.
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Transcriptional coupling of distant regulatory genes in living embryos
In Drosophila, there are extensive physical and functional associations of distant paralogous genes, including co-regulation by shared enhancers and co-transcriptional initiation over distances of nearly 250 kilobases.
- Michal Levo
- , João Raimundo
- & Michael S. Levine
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Molecular basis for the initiation of DNA primer synthesis
The molecular determinants for primer synthesis are identified within the catalytic domain of primase-polymerase enzymes, elucidating the mechanisms underlying initiation of primer synthesis.
- Arthur W. H. Li
- , Katerina Zabrady
- & Aidan J. Doherty
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Article |
Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA
Herpesvirus microRNAs interfere directly with host cell microRNA processing, thereby disrupting mitochondrial architecture, evading intrinsic host defences and driving the switch from latent to lytic infection.
- Thomas Hennig
- , Archana B. Prusty
- & Bhupesh K. Prusty
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Article
| Open AccessGene regulation by gonadal hormone receptors underlies brain sex differences
A study maps neuronal genomic targets of oestrogen receptor-α and shows how they coordinate brain sexual differentiation, concluding that the genome remains responsive to hormonal changes after structural dimorphisms have been established.
- B. Gegenhuber
- , M. V. Wu
- & J. Tollkuhn
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News & Views |
Phosphorylation found inside RNA
In an impressively thorough study, phosphorylation in the core of a transfer RNA molecule has been described for the first time, and the enzymes that add and remove the phosphate group have been characterized.
- Mark Helm
- & Yuri Motorin
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Article |
Breakage of cytoplasmic chromosomes by pathological DNA base excision repair
DNA damage during chromothripsis is caused by deoxyinosine formation on accumulated RNA–DNA hybrids in micronuclei that are then recognized by N-methyl-purine DNA glycosylase and cleaved by apurinic/apyrimidinic endonuclease.
- Shangming Tang
- , Ema Stokasimov
- & David Pellman
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Research Briefing |
Control of human protein-degradation machinery revealed
A long-standing puzzle in molecular biology is how the enzyme USP14 is activated by the proteasome and regulates protein degradation. Time-resolved cryo-electron microscopy combined with deep learning reveals this mechanism in unprecedented detail.
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Article
| Open AccessReversible RNA phosphorylation stabilizes tRNA for cellular thermotolerance
Reversible internal RNA phosphrylation contributes to thermal stability and nuclease resistance of tRNA, and cellular thermotolerance of hyperthermophiles.
- Takayuki Ohira
- , Keiichi Minowa
- & Tsutomu Suzuki
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Article |
Structure of human chromatin-remodelling PBAF complex bound to a nucleosome
Cryo-electron microscopy structures of the 12-member PBAF complex provide insights into nucleosome recognition by the complex and the role of mutations in human disease.
- Junjie Yuan
- , Kangjing Chen
- & Zhucheng Chen
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Matters Arising |
Evaluating ribosomal frameshifting in CCR5 mRNA decoding
- Yousuf A. Khan
- , Gary Loughran
- & John F. Atkins
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Article
| Open AccessIntron-mediated induction of phenotypic heterogeneity
Experiments in yeast show that introns have a role in inducing phenotypic heterogeneity and that intron-mediated regulation of ribosomal proteins confers a fitness advantage by enabling yeast populations to diversify under nutrient-scarce conditions.
- Martin Lukačišin
- , Adriana Espinosa-Cantú
- & Tobias Bollenbach
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Somatic genomic changes in single Alzheimer’s disease neurons
Analyses of single-cell whole-genome sequencing data show that somatic mutations are increased in the brain of individuals with Alzheimer’s disease compared to neurotypical individuals, with a pattern of genomic damage distinct from that of normal ageing.
- Michael B. Miller
- , August Yue Huang
- & Christopher A. Walsh
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News & Views |
Self-activated adhesion receptor proteins visualized
The inner workings of a family of proteins, known as adhesion G-protein-coupled receptors, have finally been visualized at high resolution — revealing the structural basis of their self-activation mechanism.
- Antony A. Boucard
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Article
| Open AccessNonlinear control of transcription through enhancer–promoter interactions
The transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship, and enhancer strength determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation.
- Jessica Zuin
- , Gregory Roth
- & Luca Giorgetti
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Structure of active human telomerase with telomere shelterin protein TPP1
Cryo-electron microscopy structures of human telomerase and telomerase in complex with TPP1 provide insights into the interactions of these proteins and their activities.
- Baocheng Liu
- , Yao He
- & Juli Feigon
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News & Views |
Democratizing the mapping of gene mutations to protein biophysics
A general method that quantifies and disentangles the effects of a gene’s mutations on the traits of its protein enables assessments of mutational effects on protein biophysics for many of the proteins of a living organism.
- Debora S. Marks
- & Stephen W. Michnick
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Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile
Structural analysis of Clostridioides difficile RNA polymerase in complex with fidaxomicin combined with biochemical, genetic and bioinformatic analyses identifies a key residue that determines fidaxomicin sensitivity.
- Xinyun Cao
- , Hande Boyaci
- & Elizabeth A. Campbell
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News & Views |
An added layer of repression for human genes
A protein complex called the rixosome helps to degrade RNA transcripts that linger after gene expression ceases. This discovery points to distinct roles for the rixosome in regulating chromatin in different species.
- Michael Uckelmann
- & Chen Davidovich
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Article
| Open AccessRixosomal RNA degradation contributes to silencing of Polycomb target genes
The rixosome associates with Polycomb repressive complexes and chromatin and has a role in silencing of Polycomb target gene expression in human cells via degradation of nascent RNA transcripts.
- Haining Zhou
- , Chad B. Stein
- & Danesh Moazed
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Targeting Xist with compounds that disrupt RNA structure and X inactivation
A molecule identified in a screen for compounds that bind the non-coding mouse RNA Xist blocks Xist-dependent X-chromosome inactivation, demonstrating the utility of this approach for identifying drugs that target RNA.
- Rodrigo Aguilar
- , Kerrie B. Spencer
- & Jeannie T. Lee
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Crucial role and mechanism of transcription-coupled DNA repair in bacteria
Integrated structure–function studies show that transcription-coupled DNA repair (TCR)—rather than global genomic repair—is responsible for most chromosomal repair events in bacteria, and that TCR mainly occurs independently of the Mfd translocase.
- Binod K. Bharati
- , Manjunath Gowder
- & Evgeny Nudler
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N6-methyladenosine in poly(A) tails stabilize VSG transcripts
N6-methyladenosine is enriched in poly(A) tails of VSG transcripts in Trypanosoma brucei, and when lacking result in mRNA degradation.
- Idálio J. Viegas
- , Juan Pereira de Macedo
- & Luisa M. Figueiredo
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Article
| Open AccessA TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.
- Tirosh Shapira
- , I. Abrrey Monreal
- & François Jean
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Technology Feature |
Molecular barcodes reveal tumour lineages
Researchers are blending tools from developmental biology with technologies such as cell sorting and CRISPR to gain fresh insight into cancer.
- Jyoti Madhusoodanan
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Obituary |
François Gros (1925–2022)
Co-discoverer of messenger RNA who advanced French life sciences.
- Georgina Ferry
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