Molecular biology

  • Article
    | Open Access

    Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.

    • Huan-Chang Liang
    • , Mariantonia Costanza
    •  & Olaf Merkel
  • Article
    | Open Access

    Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.

    • Jing Liu
    • , Daniela Ottaviani
    •  & François Radvanyi
  • Article
    | Open Access

    In Saccharomyces cerevisiae, unchecked proliferation of Ty1 retrotransposons is controlled by the process of copy number control (CNC), which requires the p22/p18 protein, translated from an internal transcript within the Ty1 GAG gene. Here, the authors present the 2.8 Å crystal structure of a minimal p18 from Ty1-Gag that is able to restrict Ty1 transposition and identify two dimer interfaces in p18, whose roles were probed by mutagenesis both in vitro and in vivo. As p22/p18 contains only one of two conserved domains required for retroelement Gag assembly, they propose that p22/p18-Gag interactions block the Ty1 virus-like particle assembly pathway, resulting in defective particles incapable of supporting retrotransposition.

    • Matthew A. Cottee
    • , Sean L. Beckwith
    •  & Ian A. Taylor
  • Article
    | Open Access

    KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation

    • Rajesh Sharma
    • , Kyoung-Jae Choi
    •  & Josephine C. Ferreon
  • Article
    | Open Access

    The mechanisms that allow cancer cells to survive with monosomies are poorly understood. Here the authors analyse p53-deficient monosomic cell lines using transcriptomics and proteomics, and find that impaired ribosome biogenesis and p53 downregulation are associated with sustained monosomies.

    • Narendra Kumar Chunduri
    • , Paul Menges
    •  & Zuzana Storchova
  • Article
    | Open Access

    Replicative hexameric helicases are fundamental components of replisomes. Here the authors resolve a cryo-EM structure of the E1 helicase from papillomavirus bound to a DNA replication fork, providing insights into the mechanism of DNA unwinding by these hexameric enzymes.

    • Abid Javed
    • , Balazs Major
    •  & Elena V. Orlova
  • Article
    | Open Access

    m6Am is a modification of the 5′ end of mRNAs catalyzed by PCIF1. Here, Zhang et al. show that HIV infection induces a decrease in m6Am of cellular mRNAs through Vpr-mediated PCIF1 ubiquitination and degradation, resulting in increased HIV replication through regulation of host transcription factors.

    • Qiong Zhang
    • , Yuqi Kang
    •  & Tariq M. Rana
  • Article
    | Open Access

    A strategy to control HIV-1 infection is to stably repress HIV-1 and induce “deep latency”. Here the authors show that a recombinant anti-HIV-1-1 protein can be packaged as mRNA into exosomes and delivered systemically to repress HIV-1-1 within the context of virus infected mice and achieve long term silencing of HIV-1-1 expression.

    • Surya Shrivastava
    • , Roslyn M. Ray
    •  & Kevin V. Morris
  • Article
    | Open Access

    Here, cryo-EM reconstructions of human cytomegalovirus (HCMV) virions reveal host tRNAs associated with the virion’s capsid-bound tegument protein, pp150. tRNA recruitment is mediated by the interactions specific for HCMV only, suggesting the explanation for the absence of such tRNA densities in related herpesviruses.

    • Yun-Tao Liu
    • , David Strugatsky
    •  & Z. Hong Zhou
  • Article
    | Open Access

    Transcription in archaea is known to be regulated through the recruitment of RNA polymerase to promoters. Here, the authors show that the archaeon Saccharolobus solfataricus regulates transcription globally through a rate-limiting promoter-proximal elongation step.

    • Fabian Blombach
    • , Thomas Fouqueau
    •  & Finn Werner
  • Article
    | Open Access

    The authors show that post-transcriptional regulation of the cilia-driven leftward flow target dand5 is central to symmetry breakage in frog, fish and mouse and is mediated by a 139 nt Bicc1 responsive element in the dand5 3′UTR, and they present evidence that Pkd2 regulates this Bicc1/dand5 module.

    • Markus Maerker
    • , Maike Getwan
    •  & Axel Schweickert
  • Article
    | Open Access

    Non-human primate models of autism spectrum disorder (ASD) are few and not well characterised. Here, the authors describe synaptic function and gene expression changes in a marmoset model of ASD from birth to juvenile, highlighting its similarity to features observed in human ASD.

    • Satoshi Watanabe
    • , Tohru Kurotani
    •  & Noritaka Ichinohe
  • Article
    | Open Access

    MAD2L2 — a member of the shieldin complex — is known to play important roles in DNA repair. Here the authors demonstrate how MAD2L2 dimerization mediated through SHLD2 participates in shieldin assembly and function.

    • Inge de Krijger
    • , Bastian Föhr
    •  & Jacqueline J. L. Jacobs
  • Article
    | Open Access

    CTCF is as an architectural protein involved in 3D genome folding; however its contribution to animal development has not been well characterized. Here the authors show that CTCF is not only pivotal for 3D chromatin structure and enhancer-promoter interactions in zebrafish, but it is also essential for controlling the expression of thousands of genes during development.

    • Martin Franke
    • , Elisa De la Calle-Mustienes
    •  & José L. Gómez-Skarmeta
  • Article
    | Open Access

    Epigenetic changes are implicated in Acute myeloid leukemia (AML) tumorigenesis. Here, the authors show that the ubiquitin ligase RNF5 and its substrate RBBP4 contribute to AML development by regulating epigenetic-controlled transcription which determines AML sensitivity to HDAC inhibitors.

    • Ali Khateb
    • , Anagha Deshpande
    •  & Ze’ev A. Ronai
  • Article
    | Open Access

    RAD51 is a well known player of DNA repair and homologous recombination. Here the authors reveal a function for RAD51 in protecting under-replicated DNA in mitotic human cells, promoting mitotic DNA synthesis (MiDAS) and successful chromosome segregation.

    • Isabel E. Wassing
    • , Emily Graham
    •  & Fumiko Esashi
  • Article
    | Open Access

    Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.

    • Vrutant V. Shah
    • , Aundrietta D. Duncan
    •  & Michelle Craig Barton
  • Article
    | Open Access

    Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.

    • Hiroki Sugishita
    • , Takashi Kondo
    •  & Haruhiko Koseki
  • Article
    | Open Access

    Bacteria adjust the expression of some of their metabolic enzymes through metabolite-sensing ribosome nascent chain complexes. Here the authors present a cryo-EM structure of an E. coli ribosome stalled during translation of the TnaC leader peptide and propose a model for L-Trp dependent ribosome stalling where L-Trp competes with release factor 2 for binding to the TnaC-ribosome complex.

    • Anne-Xander van der Stel
    • , Emily R. Gordon
    •  & C. Axel Innis
  • Article
    | Open Access

    The mechanisms underlying the activity of non-receptor tyrosine kinase, TNK1, in cancers are unclear. Here the authors show that MARK mediates 14-3-3 and TNK1 interaction which restrains TNK1 activity, while the release of TNK1 from 14-3-3 leads to TNK1 activation through its interaction with ubiquitin and thus results in TNK1-mediated tumor growth in vivo

    • Tsz-Yin Chan
    • , Christina M. Egbert
    •  & Joshua L. Andersen
  • Article
    | Open Access

    β-actin loss can affect gene expression and heterochromatin organization. Here the authors conduct a comprehensive genomic analysis of β-actin knockout mouse embryonic fibroblasts (MEFs) to investigate the impact of changes in β-actin levels on 3d genome architecture and chromatin remodeling activities of BAF and polycomb proteins.

    • Syed Raza Mahmood
    • , Xin Xie
    •  & Piergiorgio Percipalle
  • Article
    | Open Access

    Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice.

    • Arthur C. Sletten
    • , Jessica W. Davidson
    •  & Jean E. Schaffer
  • Article
    | Open Access

    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
  • Article
    | Open Access

    ParA is an ATPase involved in the segregation of newly replicated DNA in bacteria. Here, structures of a ParA filament bound to DNA and of ParA in various nucleotide states offer insight into its conformational changes upon DNA binding and filament assembly, including the basis for ParA’s cooperative binding to DNA.

    • Alexandra V. Parker
    • , Daniel Mann
    •  & Julien R. C. Bergeron
  • Article
    | Open Access

    Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.

    • Xin Huang
    • , Kyoung-mi Park
    •  & Thorold W. Theunissen
  • Article
    | Open Access

    Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.

    • Luca Mariani
    • , Xiaogang Guo
    •  & Elisabetta Ferretti
  • Article
    | Open Access

    Here, Kim et al. apply various sequencing techniques (RPF-seq, QTI-seq, mRNA-seq, sRNA-seq) to unravel the high-resolution, longitudinal translatome and transcriptome of SARS-CoV-2. They identify a translation initiation site in the leader sequence of all genomic and subgenomic RNAs and show its relevance for the SARS-CoV-2 translatome.

    • Doyeon Kim
    • , Sukjun Kim
    •  & Daehyun Baek
  • Article
    | Open Access

    The combination of intermittent fasting and chemotherapy can improve the response to treatment. Here, the authors show that SIRT7 activation is required to inactivate Akt during intermittent fasting and that the combination of intermittent fasting and inhibitors that block the Erk pathway can improve efficacy of treatment.

    • Xiaolong Tang
    • , Guo Li
    •  & Baohua Liu
  • Article
    | Open Access

    Ribosome profiling has become the gold standard to analyze mRNA translation dynamics, and the translation inhibitor cycloheximide (CHX) is often used in its application. Here the authors systematically demonstrate that CHX does not bias the outcome of ribosome profiling experiments in most organisms.

    • Puneet Sharma
    • , Jie Wu
    •  & Sebastian A. Leidel
  • Article
    | Open Access

    Alternative polyadenylation regulates localization, half-life and translation of mRNA isoforms. Here the authors investigate alternative polyadenylation using single cell RNA sequencing data from mouse embryos and identify 3’-UTR isoforms that are regulated across cell types and developmental time.

    • Vikram Agarwal
    • , Sereno Lopez-Darwin
    •  & Jay Shendure
  • Article
    | Open Access

    There have been reports of immune responses against Cas9 which may impair clinical use. Here the authors scan a cohort comparable to the North American population vis-à-vis distribution of MHC-II variants to identify Cas9 peptides presented by MHC-II proteins and can stimulate CD4 + T-cells.

    • Vijaya L. Simhadri
    • , Louis Hopkins
    •  & Zuben E. Sauna
  • Article
    | Open Access

    The effect of histone H4 lysine 20 methylation (H4K20me) on chromatin accessibility are not well established. Here the authors show how H4K20 methylation regulates chromatin structure and accessibility to ensure precise transcriptional outputs through the cell cycle using genome-wide approaches, in vitro biophysical assays, and NMR.

    • Muhammad Shoaib
    • , Qinming Chen
    •  & Claus S. Sørensen
  • Article
    | Open Access

    miRNAs are loaded into Argonaute protein and repress complementary mRNA targets. Here the authors show the unappreciated role of RNA binding proteins for efficient miRNA targeting and expand the current understanding of miRNA targeting.

    • Sukjun Kim
    • , Soyoung Kim
    •  & Daehyun Baek
  • Article
    | Open Access

    Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

    • Shengjiang Tan
    • , Laëtitia Kermasson
    •  & Patrick Revy
  • Article
    | Open Access

    The link between gRNA sequence and Cas9 activity is well established but the mechanism underlying this relationship is not well understood. Here the authors show that gRNA sequence primarily influences activity by dictating the time it takes for Cas9 to find the target site in a species-specific manner.

    • E. A. Moreb
    •  & M. D. Lynch
  • Article
    | Open Access

    Skeletal muscle stem cells (or satellite cells, SCs) are normally quiescent but activate and expand in response to injury. Here the authors show that induction of DHX36 helicase during SC activation promotes mRNA translation by binding to 5′UTR mRNA G-quadruplexes (rG4) in targets including Gnai2 and unwinding them.

    • Xiaona Chen
    • , Jie Yuan
    •  & Huating Wang
  • Article
    | Open Access

    Proximity biotinylation is a powerful tool to profile interactomes, but it requires genetic engineering of the target protein. Here, the authors develop a proximity biotinylation enzyme that can be directed to the target using antibodies, enabling interactome profiling of endogenous proteins or PTMs.

    • Irene Santos-Barriopedro
    • , Guido van Mierlo
    •  & Michiel Vermeulen
  • Article
    | Open Access

    Proper meiotic chromosome segregation requires mismatch repair genes MLH1 and MLH3, of which variants occur in the human population. Here, the authors use computational predictions and yeast assays to select human MLH1/3 variants for modelling in mice, observing reproductive defects from abnormal levels of crossing over.

    • Priti Singh
    • , Robert Fragoza
    •  & John C. Schimenti
  • Article
    | Open Access

    TOP1 resolves DNA supercoils by forming cleavage complexes (TOP1cc) that are trapped by TOP1 inhibitors. Here the authors provide insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG results in stabilization of TOP1cc PARylation that blocks the proteasomal degradation of TOP1cc.

    • Yilun Sun
    • , Jiji Chen
    •  & Yves Pommier
  • Article
    | Open Access

    Mesomelic dysplasia, a severe shortening and bending of the limb, has been linked to rearrangements in the HoxD cluster in humans and mice. Here the authors engineer a 1 Mb inversion including the HoxD gene cluster and use this model to provide a mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.

    • Christopher Chase Bolt
    • , Lucille Lopez-Delisle
    •  & Denis Duboule
  • Article
    | Open Access

    RNA polyadenosine tails are important for the export, translation and stability of mRNAs and play a role in non-coding RNA biogenesis. Here the authors measure yeast poly(A) tail lengths by direct RNA sequencing, revealing its dynamics in yeast exonuclease, deadenylase and poly(A) polymerase mutants.

    • Agnieszka Tudek
    • , Paweł S. Krawczyk
    •  & Andrzej Dziembowski