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| Open Access6mer seed toxicity in tumor suppressive microRNAs
Small interfering (siRNAs) can be toxic to cancer cells. Here the authors investigate the toxicity of microRNA in cancer cells by performing a siRNA screen that tests the miRNA activities of an extensive list of miRNAs with different 6mer seed sequences.
- Quan Q. Gao
- , William E. Putzbach
- & Marcus E. Peter
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Article
| Open AccessDeterminants of promoter and enhancer transcription directionality in metazoans
Divergent transcription from promoters and enhancers occurs in many species, but it is unclear if it is a general feature of all eukaryotic cis regulatory elements. Here the authors define cis regulatory elements in worms, flies, and human; and identify several differences in regulatory architecture among metazoans.
- Mahmoud M. Ibrahim
- , Aslihan Karabacak
- & Uwe Ohler
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Article
| Open AccessOptimization of carbon and energy utilization through differential translational efficiency
Microorganisms must regulate allocation of resources in nutrient-limited conditions. Here, the authors combine Ribo-seq, RNA-seq and TSS-seq to study resource allocation in the acetogen C. ljungdahlii, and show that dynamic regulation of translational efficiency of metabolic pathways is critical.
- Mahmoud M. Al-Bassam
- , Ji-Nu Kim
- & Karsten Zengler
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Article
| Open AccessA peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma
Functional peptides can be encoded by short open reading frames in non-coding RNA. Here, the authors identify a 87aa peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) that can reduce glioblastoma proliferation via interaction with PAF1 which sequentially inhibits the transcriptional elongation of some oncogenes.
- Maolei Zhang
- , Kun Zhao
- & Nu Zhang
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Article
| Open AccessLong-term positioning and polar preference of chemoreceptor clusters in E. coli
Bacterial chemoreceptors form clusters, preferably at the cell poles. Here, Koler et al. show that polar and lateral clusters exhibit distinct long-term positional dynamics and that polar bias may be due to differences in mobility of receptor complexes between the polar and lateral cell regions.
- Moriah Koler
- , Eliran Peretz
- & Ady Vaknin
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Article
| Open AccessStructural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1
Ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein that hydrolyzes both ATP and cGAMP. Here the authors present the crystal structures of the extracellular domain of mouse ENPP1 in complex with 3′3′-cGAMP and the reaction intermediate pA(3′,5′)pG and discuss mechanistic implications.
- Kazuki Kato
- , Hiroshi Nishimasu
- & Osamu Nureki
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Article
| Open AccessSlc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations
Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2.
- Victoria A. Baronas
- , Runying Y. Yang
- & Harley T. Kurata
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Article
| Open AccessAberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
TDP-43 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTD-TDP). Here, the authors identify the transcriptional elongation factor Ell as a strong modifier of TDP-43-mediated neurodegeneration through the Ell transcriptional elongation complexes LEC and SEC.
- Chia-Yu Chung
- , Amit Berson
- & Nancy M. Bonini
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Article
| Open AccessDAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity
The transcription factor DAF-16/FOXO is a downstream effector of insulin/insulin-like growth factor signaling and plays an important role in stress resistance and longevity. Here, the authors show that DAF-16/FOXO can form a complex with HLH-30/TFEB to synergistically regulate transcription of target genes in response to certain stress stimuli.
- Xin-Xuan Lin
- , Ilke Sen
- & Christian G. Riedel
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Article
| Open AccessA distinct isoform of ZNF207 controls self-renewal and pluripotency of human embryonic stem cells
Self-renewal and pluripotency of human embryonic stem cells (hESCs) depends upon the function of the transcription factor OCT4. Here, the authors identified proteins associated with the OCT4 enhancer, notably ZNF207 that maintains both pluripotency and differentiation towards ectoderm through isoform switching.
- Fang Fang
- , Ninuo Xia
- & Renee A. Reijo Pera
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Article
| Open AccessNEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress
Protein NEDDylation increases upon proteotoxic stress but the function of this response remains to be elucidated. Here, the authors show that NEDDylation contributes to the cellular defence against proteotoxicity by promoting nuclear protein aggregation and protecting the ubiquitin proteasome system.
- Chantal M. Maghames
- , Sofia Lobato-Gil
- & Dimitris P. Xirodimas
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Article
| Open AccessZZ-dependent regulation of p62/SQSTM1 in autophagy
The autophagic receptor p62 recognizes arginylated (Nt-R) substrates through its ZZ domain (p62ZZ). Here the authors identify a p62 auto regulatory mechanism and provide structural insights into the selective recognition of Nt-R by p62ZZ and further show that Nt-R binding stimulates p62 oligomerization and macroautophagy.
- Yi Zhang
- , Su Ran Mun
- & Tatiana G. Kutateladze
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Article
| Open AccessLong non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development
LncRNAs modulate diverse physiological cellular processes, however, their involvement in heme-dependent processes are not yet clear. Here the authors reveal the role of lncRNA UCA1 in erythroid cell development.
- Jinhua Liu
- , Yapu Li
- & Lihong Shi
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Article
| Open AccessCommon mechanism of transcription termination at coding and noncoding RNA genes in fission yeast
Termination of RNA polymerase II (RNAPII) transcription is an essential step of gene expression. Here the authors provide evidence that in fission yeast termination of ncRNA genes occurs by a cleavage-dependent mechanism involving recruitment of mRNA 3′ end processing factors and requires the conserved Ysh1/CPSF-73 and Dhp1/XRN2 nucleases.
- Marc Larochelle
- , Marc-Antoine Robert
- & François Bachand
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Article
| Open AccessDHX9 helicase promotes R-loop formation in cells with impaired RNA splicing
Unresolved R-loops can represent a threat to genome stability. Here the authors reveal that DHX9 helicase can promote R-loop formation in the absence of splicing factors SFPQ and SF3B3.
- Prasun Chakraborty
- , Jeffrey T. J. Huang
- & Kevin Hiom
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Article
| Open AccessMycobacterial DnaB helicase intein as oxidative stress sensor
Inteins can act as post-translational environmental sensors in vivo. Here the authors characterize two inteins present in the Mycobacterium smegmatis replicative helicase DnaB that display distinct splicing behaviors and are differentially sensitive to inhibition by biological stressors and propose that splicing inhibition could modulate DnaB levels to protect the cell against replication stress.
- Danielle S. Kelley
- , Christopher W. Lennon
- & Marlene Belfort
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Review Article
| Open AccessThe dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA
Centromeres are the chromosomal domains that regulate assembly of the components required for chromosome separation. Here the authors review how centromeres are a potential source of genome instability and link centromere aberrations and rearrangements to human diseases such as cancer.
- V. Barra
- & D. Fachinetti
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Article
| Open AccessmRNAs and lncRNAs intrinsically form secondary structures with short end-to-end distances
It was previously suggested that formation of RNA secondary structure tends to bring the 5′ and 3′ ends of RNA into close proximity. Here the authors use experimental and computational approaches to show that mRNAs and lncRNAs have an intrinsic propensity to fold into structures in which the 5′ end and 3′ end are ≤7 nm apart irrespective of length.
- Wan-Jung C. Lai
- , Mohammad Kayedkhordeh
- & Dmitri N. Ermolenko
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Article
| Open AccessDRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.
- Chaoyang Ye
- , Daniel J. Ho
- & Ajamete Kaykas
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Article
| Open AccessCaenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis
Paternal contributions to epigenetic inheritance via nucleosomes are poorly understood, as sperm in many organisms replace the majority of nucleosomes with protamines. Here the authors provide evidence that Caenorhabditis elegans sperm retain histone packaging of the genome and provide a histone-based epigenetic memory that is important for germ cell development in offspring.
- Tomoko M. Tabuchi
- , Andreas Rechtsteiner
- & Susan Strome
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Article
| Open AccessTracing the transitions from pluripotency to germ cell fate with CRISPR screening
Primordial Germ Cell-Like Cells (PGCLCs) are an in vitro model for primordial germ cell development. Here, the authors couple a novel compound reporter with CRISPR screening to identify key genes for exit from pluripotency and acquisition of PGCLC fate; specifically identifying Nr5a2 and Zfp296.
- Jamie A. Hackett
- , Yun Huang
- & M. Azim Surani
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Article
| Open AccessTridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin
Whether DNA viruses contact specific regions of host genomes or make random contacts is unclear. Here, the authors use Hi-C and show that HBV cccDNA and Ad5 DNA contact preferentially active chromatin at CpG islands for the former and at transcription start sites and enhancers for the latter.
- Pierrick Moreau
- , Axel Cournac
- & Christine Neuveut
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Article
| Open AccessHIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry
The HIV Tat protein recruits a host elongation factor from the cellular 7SK complex to the viral TAR RNA to ensure transcriptional elongation. Here, Pham et al. solve the structures of both 7SK and TAR RNAs in complex with Tat’s RNA binding domain and gain mechanistic insights into the process.
- Vincent V. Pham
- , Carolina Salguero
- & Victoria M. D’Souza
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Article
| Open AccessSHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival
T-acute lymphoblastic leukemia is an aggressive cancer. Here the authors provide insights into the functional role of SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, in T-lymphoblastic leukemia cell survival through regulating the maturation of MYC mRNA.
- Hexiu Su
- , Juncheng Hu
- & Hudan Liu
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Article
| Open AccessPrecisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions
Measuring precise protein turnover rates in animals is technically challenging at the proteomic level. Here, Fornasiero and colleagues use isotopic labeling with mass spectrometry and mathematical modeling to accurately determine protein lifetimes in the mouse brain
- Eugenio F. Fornasiero
- , Sunit Mandad
- & Silvio O. Rizzoli
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Article
| Open AccessEVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
Chr3q26 rearrangements cause overexpression of EVI1 and associate with myeloid neoplasms, but the mechanism behind this association is unclear. Here, using a novel mouse model they show that EVI1 causes premalignant myeloid expansion with suppression of other lineages through upregulation of Spi1/PU.1.
- Edward Ayoub
- , Michael P. Wilson
- & Archibald S. Perkins
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Article
| Open AccessPol μ dGTP mismatch insertion opposite T coupled with ligation reveals promutagenic DNA repair intermediate
Incorporation of mismatched nucleotides during DNA replication or repair can lead to mutagenesis. Here the authors reveal that DNA ligase can ligate NHEJ intermediates following incorporation of 8-oxodGTP or dGTP opposite T by DNA Polymerase mu (Pol mu) in vitro, which suggests that Pol mu could cause promutagenic mismatches during DSB repair.
- Melike Çağlayan
- & Samuel H. Wilson
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Article
| Open AccessDivergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages
The role of the genome structure in the establishment of the embryonic and trophoblast lineages is still not well understood. Here the authors perform promoter capture Hi-C in mouse trophoblast and embryonic stem cells and find divergent networks of repressive and active chromatin interactions between the two lineages.
- Stefan Schoenfelder
- , Borbala Mifsud
- & Miguel R. Branco
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Article
| Open AccessShu 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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Article
| Open AccessTwo high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.
- Mary L. McMaster
- , Sonja I. Berndt
- & Neil E. Caporaso
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Article
| Open AccessCryo-EM structure of the hibernating Thermus thermophilus 100S ribosome reveals a protein-mediated dimerization mechanism
During stress conditions bacterial ribosomes dimerize and form inactive but stable hibernating 100S particles, a process that is facilitated by the hibernation-promoting factor (HPF). Here the authors analyze 100S dimer formation as a function of HPF protein concentration and present the Thermus thermophilus 100S ribosome cryo-EM structure.
- Rasmus Kock Flygaard
- , Niels Boegholm
- & Lasse B. Jenner
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Article
| Open AccessLong non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling
Long noncoding RNAs have been shown to play a role in cardiovascular disease. Here, the authors identify a lncRNA named CCRR, whose downregulation in failing hearts causes cardiac conduction disturbances by altering the endocytic trafficking of Cx43.
- Yong Zhang
- , Lihua Sun
- & Baofeng Yang
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Article
| Open AccessROS-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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Article
| Open AccessSWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
The mechanism of resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations is unknown. Here, the authors demonstrate that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
- Shuai Wu
- , Nail Fatkhutdinov
- & Rugang Zhang
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Article
| Open AccessEnhanced validation of antibodies for research applications
Five validation pillars have been proposed to verify the specificity of research antibodies. Here the authors screen 6,000 antibodies from the Human Protein Atlas with these methods to provide an antibody validation resource for providers and users.
- Fredrik Edfors
- , Andreas Hober
- & Mathias Uhlen
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Article
| Open AccessFormation of the β-barrel assembly machinery complex in lipid bilayers as seen by solid-state NMR
The β-barrel assembly machinery (BAM) catalyzes β-barrel protein insertion into the outer membrane of E.coli. Here authors employ high-sensitivity solid-state NMR to reveal how the lipid environment and formation of the BamA-BamCDE complex affect BamA structure and dynamics with regards to the lateral gate and the β-barrel associated domains.
- Cecilia Pinto
- , Deni Mance
- & Marc Baldus
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Article
| Open AccessATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage
DNA damage can lead to autophagy. Here the authors reveal a molecular mechanism for ATR/Chk1 signaling-induced autophagy in response to DNA damage, through an ATR/Chk1/RhoB-mediated lysosomal recruitment of TSC complex and subsequent mTORC1 inhibition.
- Mingdong Liu
- , Taoling Zeng
- & Hong-Rui Wang
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Article
| Open AccessGenetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease
Human APOBEC3H has several haplotypes and splice variants with distinct anti-HIV-1 activities, but the genetics underlying the expression of these variants are unclear. Here, the authors identify an intronic deletion in A3H haplotype II resulting in production of the most active splice variant, which is counteracted by HIV-1 protease.
- Diako Ebrahimi
- , Christopher M. Richards
- & Reuben S. Harris
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Article
| Open AccessIntestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88
It remains unclear how microbial sensing during early-life colonization results in immune homeostasis rather than acute inflammation. Here the authors show that zebrafish larvae colonization suppresses intestinal MyD88, accounting for a considerable proportion of microbiota-induced alterations in immune setpoint.
- Bjørn E. V. Koch
- , Shuxin Yang
- & Herman P. Spaink
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Article
| Open AccessSuppressor mutations in Rpf2–Rrs1 or Rpl5 bypass the Cgr1 function for pre-ribosomal 5S RNP-rotation
During biogenesis of the eukaryotic 60S ribosome, a large rotational movement of the 5S RNP is required to achieve its mature position. By analyzing extragenic suppressors of crg1—a key factor required for rotation—the authors provide mechanistic insight into a key step of ribosome biogenesis.
- Matthias Thoms
- , Valentin Mitterer
- & Ed Hurt
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Article
| Open AccessDNA damage sensitivity of SWI/SNF-deficient cells depends on TFIIH subunit p62/GTF2H1
SWI/SNF genes are commonly found to be mutated in different cancers. Here the authors report that the remodelers BRM and BRG1 are necessary for efficient nucleotide excision repair by promoting the expression of TFIIH subunit GTF2H1.
- Cristina Ribeiro-Silva
- , Özge Z. Aydin
- & Wim Vermeulen
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Article
| Open AccessCell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape
Mitosis poses a challenge for transcriptional programs, as it is thought that several proteins lose binding on condensed chromosomes. Here, the authors analyze the chromatin-bound proteome through the cell cycle, revealing retention of most transcription factors and preservation of the regulatory landscape.
- Paul Adrian Ginno
- , Lukas Burger
- & Dirk Schübeler
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Article
| Open AccessAnalysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma
The intrinsic drivers of glioblastoma (GBM) migration are still poorly understood. Here the authors purify GBM stem cells (GSCs) from patients and profile chromatin accessibility in these cells, identifying TEAD1 as a regulator of migration in human glioblastoma.
- Jessica Tome-Garcia
- , Parsa Erfani
- & Nadejda M. Tsankova
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Article
| Open AccessRegulatory 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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Article
| Open AccessMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Around 10% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1 promoter methylation, but it is uncertain how it predicts response to PARP inhibition. Here, the authors show that homozygous BRCA1 methylation predicts response to rucaparib while heterozygous methylation of BRCA1 predicts resistance in HGSOC.
- Olga Kondrashova
- , Monique Topp
- & Clare L. Scott
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Article
| Open AccessUSP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy
USP24 has previously been reported to be involved in cancer progression. Here, the authors demonstrate that USP24 stabilizes p300 and β-TrCP to increase the levels of NF-κB and histone-3 acetylation, and decrease DNMT1 and IκB levels which promotes IL-6 expression in M2 macrophages and lung cancer cells.
- Yi-Chang Wang
- , Yu-Syuan Wu
- & Jan-Jong Hung
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Article
| Open AccessSystems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery
DNA damage induces checkpoints to ensure that damage is not transferred to the next generation, but the molecular pathways responsible for checkpoint recovery are not clear. Here the authors show that the nutrient sensor mTORC1 is a determinant for G2/M checkpoint recovery through regulation of cyclin B1 and PLK1 expression.
- Hui-Ju Hsieh
- , Wei Zhang
- & Guang Peng
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Article
| Open AccessIntracellular nucleosomes constrain a DNA linking number difference of −1.26 that reconciles the Lk paradox
There had been an enduring discrepancy between theoretical and observed measurement of the DNA linking number (∆Lk) constrained by nucleosomes. Here the authors provide measurements of the ∆Lk constrained by individual nucleosomes in native chromatin that reconcile this discrepancy.
- Joana Segura
- , Ricky S. Joshi
- & Joaquim Roca
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Article
| Open AccessRegulatory mechanisms of incomplete huntingtin mRNA splicing
Incomplete splicing of HTT results in the production of the highly pathogenic exon 1 HTT protein. Here the authors identify the necessary intronic regions and the underlying mechanisms that contribute to this process.
- Andreas Neueder
- , Anaelle A. Dumas
- & Gillian P. Bates
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