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Article
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FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells
Here the authors show that PARPi efficacy along with the fitness of BRCA1 deficient cells relies on FANCJ, which maintains S-phase PARP1 activity by preventing its sequestration with MSH2 on G-quadruplexes.
- Ke Cong
- , Nathan MacGilvary
- & Sharon B. Cantor
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Article
| Open Access
Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier
DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.
- Zhiqian Li
- , Lang You
- & Ethan Bier
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Article
| Open Access
Ion mobility-tandem mass spectrometry of mucin-type O-glycans
Currently, only a few specialized labs can characterize O-glycans. The present study couples high-resolution ion mobility spectrometry with tandem mass spectrometry to efficiently identify complex O-glycan structures in clinical samples.
- Leïla Bechtella
- , Jin Chunsheng
- & Kevin Pagel
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Article
| Open Access
Structure of the human Bre1 complex bound to the nucleosome
The structure of the nucleosome-bound human Bre1 complex reveals that its two RING domains bind the acidic patch and nucleosomal DNA, directing the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. The binding mode suggests a possible regulatory mechanism through nucleosomal DNA flexibility.
- Shuhei Onishi
- , Kotone Uchiyama
- & Toru Sengoku
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Article
| Open Access
The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open Access
Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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Article
| Open Access
BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open Access
GAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open Access
p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice
DNA repair deficiency can cause tissue-specific phenotypes in humans and mice. Here, the authors find that p53 drives different, but tissue-specific responses despite the same defect in DNA repair. p53 drives blood stem cell loss but restrains liver polyploidisation in the absence of Ercc1.
- Ross J. Hill
- , Nazareno Bona
- & Gerry P. Crossan
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Article
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Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open Access
Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.
- Ashenafi Bulle
- , Peng Liu
- & Kian-Huat Lim
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Article
| Open Access
Extended stop codon context predicts nonsense codon readthrough efficiency in human cells
Stop codon readthrough, the ribosomal bypass of mRNA nonsense codons, has therapeutic potential for diseases caused by nonsense mutations. Here, the authors used machine learning to define readthrough-conducive mRNA sequences and predict specific CFTR alleles likely amenable to readthrough therapy.
- Kotchaphorn Mangkalaphiban
- , Lianwu Fu
- & Allan Jacobson
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Article
| Open Access
A universal molecular control for DNA, mRNA and protein expression
Multi-omics analyses powerfully combine gene expression and translation, however no available controls can be used across these techniques. Here the authors develop pREF, a universal control construct designed for use in DNA, RNA and protein analyses.
- Helen M. Gunter
- , Scott E. Youlten
- & Tim R. Mercer
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Article
| Open Access
One-Tip enables comprehensive proteome coverage in minimal cells and single zygotes
Traditional proteomics methods are complex and resource-intensive. Here, the authors develop One-Tip, a highly simplified approach that enables efficient, sensitive, and comprehensive analysis across various sample types, from blood plasma to single cells.
- Zilu Ye
- , Pierre Sabatier
- & Jesper V. Olsen
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Article
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Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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Article
| Open Access
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
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Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Article
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Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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Article
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VCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates
p97/VCP, a nexus of the ubiquitin system, recognizes and unfolds ubiquitylated substrates via multiple cofactors. Here, the authors identify VCF1, a nuclear cofactor promoting p97 recruitment to, and proteasomal degradation of, ubiquitylated targets.
- Ann Schirin Mirsanaye
- , Saskia Hoffmann
- & Niels Mailand
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| Open Access
The SecM arrest peptide traps a pre-peptide bond formation state of the ribosome
Stalling of ribosomes by the nascent polypeptide chain is widely used to regulate gene expression. Here, Gersteuer et al determine cryo-EM structures of SecM-stalled ribosomes revealing the mechanism by which the SecM peptide arrests translation.
- Felix Gersteuer
- , Martino Morici
- & Daniel N. Wilson
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Article
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Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto
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Article
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RAPP-containing arrest peptides induce translational stalling by short circuiting the ribosomal peptidyltransferase activity
Translation of RAPP (Arg-AlaPro-Pro) motifs induces ribosome stalling. Here, structures of RAPP-stalled ribosomes reveal that RAPP motifs short circuit the ribosomal peptidyltransferase activity to induce stalling.
- Martino Morici
- , Sara Gabrielli
- & Daniel N. Wilson
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Article
| Open Access
NAP-seq reveals multiple classes of structured noncoding RNAs with regulatory functions
The genome-wide prevalence, mechanism and function of noncapped RNAs (napRNAs) are currently poorly understood. Here, the authors develop a method called NAP-seq, to globally profile the full-length sequences of napRNAs, revealing several classes of structured noncoding RNAs.
- Shurong Liu
- , Junhong Huang
- & Jianhua Yang
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Article
| Open Access
Engineering intelligent chassis cells via recombinase-based MEMORY circuits
The unification of decision-making, communication, and memory would enable the programming of intelligent biotic systems. Here, the authors achieve this goal by engineering E. coli chassis cells with an array of inducible recombinases that mediate diverse genetic programs.
- Brian D. Huang
- , Dowan Kim
- & Corey J. Wilson
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Article
| Open Access
Evolutionary origin of Hoxc13-dependent skin appendages in amphibians
Hair is the main skin appendage of mammals. Here, the authors show that claws of clawed frogs and hair contain homologous keratins and depend on the same transcription factor, Hoxc13, suggesting a common evolutionary origin of these skin appendages.
- Marjolein Carron
- , Attila Placido Sachslehner
- & Leopold Eckhart
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Article
| Open Access
Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer. This study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their substrate selectivity.
- Ambrocio Sanchez
- , Pedro Ortega
- & Rémi Buisson
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Article
| Open Access
Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis
MALAT1 is a long non-coding RNA that is known to suppress breast cancer lung metastasis. Here the authors show that MALAT1 is downregulated during osteoclastogenesis and its loss derepresses Tead3, promoting Nfatc1-mediated osteoclast differentiation and enhancing bone metastasis.
- Yang Zhao
- , Jingyuan Ning
- & Li Ma
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Article
| Open Access
The spliceosome-associated protein CWC15 promotes miRNA biogenesis in Arabidopsis
CWC15 is a spliceosome-associated protein in Arabidopsis. Here the authors reports a multifaceted role of CWC15 in promoting microRNA (miRNA) biogenesis by binding to miRNA promoters and interacting with microprocessor components.
- Bangjun Zhou
- , Huihui Yu
- & Bin Yu
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Article
| Open Access
Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Here the authors uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in leukemia. The work pointed to the potential of targeting the posttranscriptional circuitry via CNOT3 as a therapeutic vulnerability in acute myeloid leukemia.
- Maryam Ghashghaei
- , Yilin Liu
- & Ly P. Vu
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Article
| Open Access
CRISPR-powered quantitative keyword search engine in DNA data storage
Targeting the files containing content-of-interest is a challenge in DNA data storage. Here, the authors develop a CRISPR-powered search engine to quantitatively identify the keyword in files stored in DNA.
- Jiongyu Zhang
- , Chengyu Hou
- & Changchun Liu
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Article
| Open Access
piRNA loading triggers MIWI translocation from the intermitochondrial cement to chromatoid body during mouse spermatogenesis
piRNA processing factors and piRNA/PIWI complex are found in intermitochondrial cement (IMC) and chromatoid body (CB). Here, the authors show that piRNA loading orchestrates MIWI translocation from the IMC to CB, demonstrating its crucial role in spermatogenesis.
- Huan Wei
- , Jie Gao
- & Mo-Fang Liu
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Article
| Open Access
Repurposing CRISPR-Cas13 systems for robust mRNA trans-splicing
The ability to edit large stretches of mRNA transcripts remains a significant challenge. Here, the authors demonstrate that CRISPR-Cas13 systems can be repurposed to assist trans-splicing of exogenous RNA fragments into an endogenous pre-mRNA transcript, a method termed CRISPR Assisted mRNA Fragment Trans-splicing (CRAFT).
- David N. Fiflis
- , Nicolas A. Rey
- & Aravind Asokan
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Article
| Open Access
NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia
NME3 is a member of NDPK family. Here, Chen et. al., discover that histidine phosphorylatable NME3 is required for hypoxia-induced mitophagy via PA-dependent interaction with Drp1, which is protected from MUL1-mediated ubiquitination for mitophagy.
- Chih-Wei Chen
- , Chi Su
- & Zee-Fen Chang
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Article
| Open Access
Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity
Toll/interleukin-1 receptor domain-containing proteins can catabolize NAD+. Here, Wang et al show that these proteins can also function as NAD-RNA decapping enzymes by releasing the NAM moiety from the NAD-RNA, resulting in the regulation of gene expression.
- Xufeng Wang
- , Dongli Yu
- & Xuemei Chen
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Article
| Open Access
ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway
Here, the authors characterise the zinc finger protein ZNF827 as a single stranded DNA binding protein that accumulates at stalled replication forks to activate the ATR-CHK1 pathway and engage homologous-recombination mediated DNA repair.
- Sile F. Yang
- , Christopher B. Nelson
- & Hilda A. Pickett
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Article
| Open Access
Functionalized graphene-oxide grids enable high-resolution cryo-EM structures of the SNF2h-nucleosome complex without crosslinking
Nucleosome-protein complexes stick to the air-water interface and denature upon plunge freezing for cryoEM. Here, authors Chio and Palovcak et al. develop EM grids that protect such complexes and use these grids to study the ATP-dependent chromatin remodeler SNF2h.
- Un Seng Chio
- , Eugene Palovcak
- & Yifan Cheng
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Article
| Open Access
Single-cell division tracing and transcriptomics reveal cell types and differentiation paths in the regenerating lung
This study uses single-cell transcriptomics to examine how lung cells respond to targeted damage. The authors employ genetically modified mouse models and cell sorting to enrich for rare, actively dividing cells, revealing cell types/states and alternative differentiation paths.
- Leila R. Martins
- , Lina Sieverling
- & Claudia Scholl
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| Open Access
Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system
Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer. Here, authors develop a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation programs, showing that SMARCB1 restricts differentiation, and nominating other regulators with therapeutic potential.
- Sandor Spisak
- , David Chen
- & Nilay S. Sethi
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Article
| Open Access
dCas13-mediated translational repression for accurate gene silencing in mammalian cells
Current gene silencing tools can have drawbacks. Here the authors report CRISPRδ, an approach for translational silencing, harnessing catalytically inactive Cas13 proteins (dCas13): they also show that fusion of a translational repressor to dCas13 further improved the performance.
- Antonios Apostolopoulos
- , Naohiro Kawamoto
- & Shintaro Iwasaki
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Article
| Open Access
YTHDF2 governs muscle size through a targeted modulation of proteostasis
This study highlights the role of YTHDF2, a protein that recognizes m6A-modified RNA, in determining muscle size. The authors show a post-transcriptional mechanism regulating muscle catabolism and growth, prompting interest to address muscle wasting.
- Christopher J. Gilbert
- , Charles P. Rabolli
- & Federica Accornero
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Article
| Open Access
Interrogations of single-cell RNA splicing landscapes with SCASL define new cell identities with physiological relevance
RNA splicing serves as a critical layer of gene expression regulation. Here, authors introduce SCASL for investigating the heterogeneity of RNA splicing landscapes at single-cell resolution, offering a novel scheme for classifying cell identities with physiological relevance.
- Xianke Xiang
- , Yao He
- & Xuerui Yang
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Article
| Open Access
GWAS reveals determinants of mobilization rate and dynamics of an active endogenous retrovirus of cattle
Endogenous retroviruses constitute 5–10% of mammalian genome space. This study characterize the bovine ERVK[2-1- LTR] clade showing that its activity varies between individuals as a function of the number of inherited autonomous elements, yet that most de novo insertions are non-autonomous elements lacking functional genes.
- Lijing Tang
- , Benjamin Swedlund
- & Carole Charlier
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Article
| Open Access
GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer
GRB2 is known for its role in Receptor Tyrosine Kinase and RAS signaling. Here the authors unveil a GRB2 function and mechanism for DNA replication fork protection. GRB2 alleviates oncogenic replication stress, and in doing so, averts cancer immune destruction by inhibiting cGAS/STING and pro-inflammatory cytokine production.
- Zu Ye
- , Shengfeng Xu
- & Zamal Ahmed
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Article
| Open Access
N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration
Here, Ma et al. investigate the translational profile of cardiac regeneration, pointing to Nat10 as a key regulator of cardiomyocyte proliferative potential, and describing how it regulates cardiac gene expression.
- Wenya Ma
- , Yanan Tian
- & Benzhi Cai
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Article
| Open Access
Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress
The genetic factors involved in liver injury remain largely unknown. Here, the authors show that ASGR1 deficiency induces liver injury by activating the GP73-mediated ER stress pathway, suggesting its role as a genetic determinant influencing susceptibility to liver injury.
- Zhe Zhang
- , Xiang Kai Leng
- & Jiang Wei Wu
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Article
| Open Access
A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open Access
Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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Article
| Open Access
Enhancing prime editor activity by directed protein evolution in yeast
Compared to traditional Cas9 nucleases prime editors (PEs) are less active. Here the authors use OrthoRep, a yeast-based platform for directed protein evolution to enhance the editing efficiency of PEs: they identify mutations that have a positive effect on kinetics and use this knowledge to generate an efficient in vivo PE.
- Yanik Weber
- , Desirée Böck
- & Gerald Schwank
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Article
| Open Access
Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes
FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.
- Sowmiya Palani
- , Yuka Machida
- & Yuichi J. Machida
Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed RepairBrowse broader subjects
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- Cell division
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- Post-translational modifications
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