journal
https://read.qxmd.com/read/38452764/dissection-of-a-ctcf-topological-boundary-uncovers-principles-of-enhancer-oncogene-regulation
#21
JOURNAL ARTICLE
Kyung Lock Kim, Gilbert J Rahme, Viraat Y Goel, Chadi A El Farran, Anders S Hansen, Bradley E Bernstein
Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin...
February 28, 2024: Molecular Cell
https://read.qxmd.com/read/38447580/glycerophosphodiesters-inhibit-lysosomal-phospholipid-catabolism-in-batten-disease
#22
JOURNAL ARTICLE
Kwamina Nyame, Andy Hims, Aya Aburous, Nouf N Laqtom, Wentao Dong, Uche N Medoh, Julia C Heiby, Jian Xiong, Alessandro Ori, Monther Abu-Remaileh
Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models...
February 28, 2024: Molecular Cell
https://read.qxmd.com/read/38428433/triaging-of-%C3%AE-helical-proteins-to-the-mitochondrial-outer-membrane-by-distinct-chaperone-machinery-based-on-substrate-topology
#23
JOURNAL ARTICLE
Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman
Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse proteins remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways that act on substrates based on their topology...
February 27, 2024: Molecular Cell
https://read.qxmd.com/read/38447581/structural-atlas-of-human-primary-micrornas-generated-by-shape-map
#24
JOURNAL ARTICLE
S Chan Baek, Boseon Kim, Harim Jang, Kijun Kim, Il-Soo Park, Dal-Hee Min, V Narry Kim
MicroRNA (miRNA) maturation is critically dependent on structural features of primary transcripts (pri-miRNAs). However, the scarcity of determined pri-miRNA structures has limited our understanding of miRNA maturation. Here, we employed selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), a high-throughput RNA structure probing method, to unravel the secondary structures of 476 high-confidence human pri-miRNAs. Our SHAPE-based structures diverge substantially from those inferred solely from computation, particularly in the apical loop and basal segments, underlining the need for experimental data in RNA structure prediction...
February 26, 2024: Molecular Cell
https://read.qxmd.com/read/38423013/the-proteomic-landscape-of-genotoxic-stress-induced-micronuclei
#25
JOURNAL ARTICLE
Kate M MacDonald, Shahbaz Khan, Brian Lin, Rose Hurren, Aaron D Schimmer, Thomas Kislinger, Shane M Harding
Micronuclei (MN) are induced by various genotoxic stressors and amass nuclear- and cytoplasmic-resident proteins, priming the cell for MN-driven signaling cascades. Here, we measured the proteome of micronuclear, cytoplasmic, and nuclear fractions from human cells exposed to a panel of six genotoxins, comprehensively profiling their MN protein landscape. We find that MN assemble a proteome distinct from both surrounding cytoplasm and parental nuclei, depleted of spliceosome and DNA damage repair components while enriched for a subset of the replisome...
February 22, 2024: Molecular Cell
https://read.qxmd.com/read/38401542/bidirectional-substrate-shuttling-between-the-26s-proteasome-and-the-cdc48-atpase-promotes-protein-degradation
#26
JOURNAL ARTICLE
Hao Li, Zhejian Ji, Joao A Paulo, Steven P Gygi, Tom A Rapoport
Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1...
February 22, 2024: Molecular Cell
https://read.qxmd.com/read/38428434/structure-of-the-multi-subunit-chloroplast-rna-polymerase
#27
JOURNAL ARTICLE
Paula F V do Prado, Frederik M Ahrens, Monique Liebers, Noah Ditz, Hans-Peter Braun, Thomas Pfannschmidt, Hauke S Hillen
Chloroplasts contain a dedicated genome that encodes subunits of the photosynthesis machinery. Transcription of photosynthesis genes is predominantly carried out by a plastid-encoded RNA polymerase (PEP), a nearly 1 MDa complex composed of core subunits with homology to eubacterial RNA polymerases (RNAPs) and at least 12 additional chloroplast-specific PEP-associated proteins (PAPs). However, the architecture of this complex and the functions of the PAPs remain unknown. Here, we report the cryo-EM structure of a 19-subunit PEP complex from Sinapis alba (white mustard)...
February 21, 2024: Molecular Cell
https://read.qxmd.com/read/38423014/a-di-acetyl-decorated-chromatin-signature-couples-liquid-condensation-to-suppress-dna-end-synapsis
#28
JOURNAL ARTICLE
Kaiwen Bao, Yanhui Ma, Yuan Li, Xilin Shen, Jiao Zhao, Shanshan Tian, Chunyong Zhang, Can Liang, Ziyan Zhao, Ying Yang, Kai Zhang, Na Yang, Fei-Long Meng, Jihui Hao, Jie Yang, Tao Liu, Zhi Yao, Ding Ai, Lei Shi
Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70-KU80, LIG4, XRCC4, and XLF, is central to non-homologous end joining (NHEJ) repair of chromatinized DNA double-strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells...
February 21, 2024: Molecular Cell
https://read.qxmd.com/read/38387462/denaturing-purifications-demonstrate-that-prc2-and-other-widely-reported-chromatin-proteins-do-not-appear-to-bind-directly-to-rna-in%C3%A2-vivo
#29
JOURNAL ARTICLE
Jimmy K Guo, Mario R Blanco, Ward G Walkup, Grant Bonesteele, Carl R Urbinati, Abhik K Banerjee, Amy Chow, Olivia Ettlin, Mackenzie Strehle, Parham Peyda, Enrique Amaya, Vickie Trinh, Mitchell Guttman
Polycomb repressive complex 2 (PRC2) is reported to bind to many RNAs and has become a central player in reports of how long non-coding RNAs (lncRNAs) regulate gene expression. Yet, there is a growing discrepancy between the biochemical evidence supporting specific lncRNA-PRC2 interactions and functional evidence demonstrating that PRC2 is often dispensable for lncRNA function. Here, we revisit the evidence supporting RNA binding by PRC2 and show that many reported interactions may not occur in vivo. Using denaturing purification of in vivo crosslinked RNA-protein complexes in human and mouse cell lines, we observe a loss of detectable RNA binding to PRC2 and chromatin-associated proteins previously reported to bind RNA (CTCF, YY1, and others), despite accurately mapping bona fide RNA-binding sites across others (SPEN, TET2, and others)...
February 20, 2024: Molecular Cell
https://read.qxmd.com/read/38382526/cullin-ring-ligases-employ-geometrically-optimized-catalytic-partners-for-substrate-targeting
#30
JOURNAL ARTICLE
Jerry Li, Nicholas Purser, Joanna Liwocha, Daniel C Scott, Holly A Byers, Barbara Steigenberger, Spencer Hill, Ishita Tripathi-Giesgen, Trent Hinkle, Fynn M Hansen, J Rajan Prabu, Senthil K Radhakrishnan, Donald S Kirkpatrick, Kurt M Reichermeier, Brenda A Schulman, Gary Kleiger
Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming...
February 20, 2024: Molecular Cell
https://read.qxmd.com/read/38402612/discovery-of-cytosine-deaminases-enables-base-resolution-methylome-mapping-using-a-single-enzyme
#31
JOURNAL ARTICLE
Romualdas Vaisvila, Sean R Johnson, Bo Yan, Nan Dai, Billal M Bourkia, Minyong Chen, Ivan R Corrêa, Erbay Yigit, Zhiyi Sun
Deaminases have important uses in modification detection and genome editing. However, the range of applications is limited by the small number of characterized enzymes. To expand the toolkit of deaminases, we developed an in vitro approach that bypasses a major hurdle with their toxicity in cells. We assayed 175 putative cytosine deaminases on a variety of substrates and found a broad range of activity on double- and single-stranded DNA in various sequence contexts, including CpG-specific deaminases and enzymes without sequence preference...
February 14, 2024: Molecular Cell
https://read.qxmd.com/read/38387461/single-molecule-tracking-reveals-the-functional-allocation-in%C3%A2-vivo-interactions-and-spatial-organization-of-universal-transcription-factor-nusg
#32
JOURNAL ARTICLE
Hafez El Sayyed, Oliver J Pambos, Mathew Stracy, Max E Gottesman, Achillefs N Kapanidis
During transcription elongation, NusG aids RNA polymerase by inhibiting pausing, promoting anti-termination on rRNA operons, coupling transcription with translation on mRNA genes, and facilitating Rho-dependent termination. Despite extensive work, the in vivo functional allocation and spatial distribution of NusG remain unknown. Using single-molecule tracking and super-resolution imaging in live E. coli cells, we found NusG predominantly in a chromosome-associated population (binding to RNA polymerase in elongation complexes) and a slowly diffusing population complexed with the 30S ribosomal subunit; the latter provides a "30S-guided" path for NusG into transcription elongation...
February 14, 2024: Molecular Cell
https://read.qxmd.com/read/38401543/distinct-negative-elongation-factor-conformations-regulate-rna-polymerase-ii-promoter-proximal-pausing
#33
JOURNAL ARTICLE
Bonnie G Su, Seychelle M Vos
Metazoan gene expression regulation involves pausing of RNA polymerase (Pol II) in the promoter-proximal region of genes and is stabilized by DSIF and NELF. Upon depletion of elongation factors, NELF appears to accompany elongating Pol II past pause sites; however, prior work indicates that NELF prevents Pol II elongation. Here, we report cryoelectron microscopy structures of Pol II-DSIF-NELF complexes with NELF in two distinct conformations corresponding to paused and poised states. The paused NELF state supports Pol II stalling, whereas the poised NELF state enables transcription elongation as it does not support a tilted RNA-DNA hybrid...
February 10, 2024: Molecular Cell
https://read.qxmd.com/read/38377994/transcription-factor-exchange-enables-prolonged-transcriptional-bursts
#34
JOURNAL ARTICLE
Wim Pomp, Joseph V W Meeussen, Tineke L Lenstra
Single-molecule imaging inside living cells has revealed that transcription factors (TFs) bind to DNA transiently, but a long-standing question is how this transient binding is related to transcription activation. Here, we devised a microscopy method to simultaneously measure transient TF binding at a single locus and the effect of these binding events on transcription. We show that DNA binding of the yeast TF Gal4 activates transcription of a target gene within a few seconds, with at least ∼20% efficiency and with a high initiation rate of ∼1 RNA/s...
February 9, 2024: Molecular Cell
https://read.qxmd.com/read/38377993/protein-language-models-assisted-optimization-of-a-uracil-n-glycosylase-variant-enables-programmable-t-to-g-and-t-to-c-base-editing
#35
JOURNAL ARTICLE
Yan He, Xibin Zhou, Chong Chang, Ge Chen, Weikuan Liu, Geng Li, Xiaoqi Fan, Mingsun Sun, Chensi Miao, Qianyue Huang, Yunqing Ma, Fajie Yuan, Xing Chang
Current base editors (BEs) use DNA deaminases, including cytidine deaminase in cytidine BE (CBE) or adenine deaminase in adenine BE (ABE), to facilitate transition nucleotide substitutions. Combining CBE or ABE with glycosylase enzymes can induce limited transversion mutations. Nonetheless, a critical demand remains for BEs capable of generating alternative mutation types, such as T>G corrections. In this study, we leveraged pre-trained protein language models to optimize a uracil-N-glycosylase (UNG) variant with altered specificity for thymines (eTDG)...
February 9, 2024: Molecular Cell
https://read.qxmd.com/read/38377992/ufl1-ablation-in-t%C3%A2-cells-suppresses-pd-1%C3%A2-ufmylation-to-enhance-anti-tumor-immunity
#36
JOURNAL ARTICLE
Chuan He, Xixin Xing, Hsin-Yi Chen, Minling Gao, Jie Shi, Bolin Xiang, Xiangling Xiao, Yishuang Sun, Haisheng Yu, Gaoshan Xu, Yingmeng Yao, Zuosong Xie, Yujie Xing, Bugi Ratno Budiarto, Shih-Yu Chen, Yang Gao, Yu-Ru Lee, Jinfang Zhang
UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice...
February 9, 2024: Molecular Cell
https://read.qxmd.com/read/38359824/specialized-replication-mechanisms-maintain-genome-stability-at-human-centromeres
#37
JOURNAL ARTICLE
Andrea Scelfo, Annapaola Angrisani, Marco Grillo, Bethany M Barnes, Francesc Muyas, Carolin M Sauer, Chin Wei Brian Leung, Marie Dumont, Marine Grison, David Mazaud, Mickaël Garnier, Laetitia Guintini, Louisa Nelson, Fumiko Esashi, Isidro Cortés-Ciriano, Stephen S Taylor, Jérôme Déjardin, Therese Wilhelm, Daniele Fachinetti
The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome...
February 7, 2024: Molecular Cell
https://read.qxmd.com/read/38359823/c19orf84-connects-pirna-and-dna-methylation-machineries-to-defend-the-mammalian-germ-line
#38
JOURNAL ARTICLE
Ansgar Zoch, Gabriela Konieczny, Tania Auchynnikava, Birgit Stallmeyer, Nadja Rotte, Madeleine Heep, Rebecca V Berrens, Martina Schito, Yuka Kabayama, Theresa Schöpp, Sabine Kliesch, Brendan Houston, Liina Nagirnaja, Moira K O'Bryan, Kenneth I Aston, Donald F Conrad, Juri Rappsilber, Robin C Allshire, Atlanta G Cook, Frank Tüttelmann, Dónal O'Carroll
In the male mouse germ line, PIWI-interacting RNAs (piRNAs), bound by the PIWI protein MIWI2 (PIWIL4), guide DNA methylation of young active transposons through SPOCD1. However, the underlying mechanisms of SPOCD1-mediated piRNA-directed transposon methylation and whether this pathway functions to protect the human germ line remain unknown. We identified loss-of-function variants in human SPOCD1 that cause defective transposon silencing and male infertility. Through the analysis of these pathogenic alleles, we discovered that the uncharacterized protein C19ORF84 interacts with SPOCD1...
February 7, 2024: Molecular Cell
https://read.qxmd.com/read/38340717/the-hri-branch-of-the-integrated-stress-response-selectively-triggers-mitophagy
#39
JOURNAL ARTICLE
Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan
To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy...
February 6, 2024: Molecular Cell
https://read.qxmd.com/read/38340716/persistence-of-backtracking-by-human-rna-polymerase-ii
#40
JOURNAL ARTICLE
Kevin B Yang, Aviram Rasouly, Vitaly Epshtein, Criseyda Martinez, Thao Nguyen, Ilya Shamovsky, Evgeny Nudler
RNA polymerase II (RNA Pol II) can backtrack during transcription elongation, exposing the 3' end of nascent RNA. Nascent RNA sequencing can approximate the location of backtracking events that are quickly resolved; however, the extent and genome-wide distribution of more persistent backtracking are unknown. Consequently, we developed a method to directly sequence the extruded, "backtracked" 3' RNA. Our data show that RNA Pol II slides backward more than 20 nt in human cells and can persist in this backtracked state...
February 6, 2024: Molecular Cell
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