journal
https://read.qxmd.com/read/38604172/three-step-mechanism-of-promoter-escape-by-rna-polymerase-ii
#1
JOURNAL ARTICLE
Yumeng Zhan, Frauke Grabbe, Elisa Oberbeckmann, Christian Dienemann, Patrick Cramer
The transition from transcription initiation to elongation is highly regulated in human cells but remains incompletely understood at the structural level. In particular, it is unclear how interactions between RNA polymerase II (RNA Pol II) and initiation factors are broken to enable promoter escape. Here, we reconstitute RNA Pol II promoter escape in vitro and determine high-resolution structures of initially transcribing complexes containing 8-, 10-, and 12-nt ordered RNAs and two elongation complexes containing 14-nt RNAs...
April 5, 2024: Molecular Cell
https://read.qxmd.com/read/38604173/response-to-learning-from-chromatin-reconstitution-pioneering-factors-enabling-nucleosome-remodelers
#2
LETTER
Kami Ahmad, Sandipan Brahma, Steven Henikoff
No abstract text is available yet for this article.
April 3, 2024: Molecular Cell
https://read.qxmd.com/read/38604171/safb-restricts-contact-domain-boundaries-associated-with-l1-chimeric-transcription
#3
JOURNAL ARTICLE
Yaqiang Hong, Luyao Bie, Tao Zhang, Xiaohan Yan, Guangpu Jin, Zhuo Chen, Yang Wang, Xiufeng Li, Gaofeng Pei, Yongyan Zhang, Yantao Hong, Liang Gong, Pilong Li, Wei Xie, Yanfen Zhu, Xiaohua Shen, Nian Liu
Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and causes disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (RNA Pol IIs), express L1 chimeric transcripts, and create contact domain boundaries in human cells. This impact of L1 is restricted by a nuclear matrix protein scaffold attachment factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit RNA Pol II enrichment...
April 2, 2024: Molecular Cell
https://read.qxmd.com/read/38599210/an-rna-dependent-and-phase-separated-active-subnuclear-compartment-safeguards-repressive-chromatin-domains
#4
JOURNAL ARTICLE
Luigi Lerra, Martina Panatta, Dominik Bär, Isabella Zanini, Jennifer Yihong Tan, Agnese Pisano, Chiara Mungo, Célia Baroux, Vikram Govind Panse, Ana C Marques, Raffaella Santoro
The nucleus is composed of functionally distinct membraneless compartments that undergo phase separation (PS). However, whether different subnuclear compartments are connected remains elusive. We identified a type of nuclear body with PS features composed of BAZ2A that associates with active chromatin. BAZ2A bodies depend on RNA transcription and BAZ2A non-disordered RNA-binding TAM domain. Although BAZ2A and H3K27me3 occupancies anticorrelate in the linear genome, in the nuclear space, BAZ2A bodies contact H3K27me3 bodies...
April 2, 2024: Molecular Cell
https://read.qxmd.com/read/38593806/time-resolved-profiling-of-rna-binding-proteins-throughout-the-mrna-life-cycle
#5
JOURNAL ARTICLE
Yeon Choi, Buyeon Um, Yongwoo Na, Jeesoo Kim, Jong-Seo Kim, V Narry Kim
mRNAs continually change their protein partners throughout their lifetimes, yet our understanding of mRNA-protein complex (mRNP) remodeling is limited by a lack of temporal data. Here, we present time-resolved mRNA interactome data by performing pulse metabolic labeling with photoactivatable ribonucleoside in human cells, UVA crosslinking, poly(A)+ RNA isolation, and mass spectrometry. This longitudinal approach allowed the quantification of over 700 RNA binding proteins (RBPs) across ten time points. Overall, the sequential order of mRNA binding aligns well with known functions, subcellular locations, and molecular interactions...
April 2, 2024: Molecular Cell
https://read.qxmd.com/read/38593805/blm-helicase-unwinds-lagging-strand-substrates-to-assemble-the-alt-telomere-damage-response
#6
JOURNAL ARTICLE
Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Aravind Krishnan, Youngho Kwon, Patrick Sung, Roger A Greenberg
The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA)...
April 2, 2024: Molecular Cell
https://read.qxmd.com/read/38593804/enhancer-switching-in-cell-lineage-priming-is-linked-to-erna-brg1-s-at-hook-and-swi-snf-recruitment
#7
JOURNAL ARTICLE
Dhurjhoti Saha, Srinivas Animireddy, Junwoo Lee, Anna Thommen, McKenzie M Murvin, Yue Lu, Mauro J Calabrese, Blaine Bartholomew
RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the two stages...
March 29, 2024: Molecular Cell
https://read.qxmd.com/read/38604174/learning-from-chromatin-reconstitution-pioneer-factors-enabling-nucleosome-remodelers
#8
LETTER
Ken Zaret
No abstract text is available yet for this article.
March 26, 2024: Molecular Cell
https://read.qxmd.com/read/38569554/ddx21-mediates-co-transcriptional-rna-m-6-a-modification-to-promote-transcription-termination-and-genome-stability
#9
JOURNAL ARTICLE
Jin-Dong Hao, Qian-Lan Liu, Meng-Xia Liu, Xing Yang, Liu-Ming Wang, Si-Yi Su, Wen Xiao, Meng-Qi Zhang, Yi-Chang Zhang, Lan Zhang, Yu-Sheng Chen, Yun-Gui Yang, Jie Ren
N6-methyladenosine (m6 A) is a crucial RNA modification that regulates diverse biological processes in human cells, but its co-transcriptional deposition and functions remain poorly understood. Here, we identified the RNA helicase DDX21 with a previously unrecognized role in directing m6 A modification on nascent RNA for co-transcriptional regulation. DDX21 interacts with METTL3 for co-recruitment to chromatin through its recognition of R-loops, which can be formed co-transcriptionally as nascent transcripts hybridize onto the template DNA strand...
March 26, 2024: Molecular Cell
https://read.qxmd.com/read/38537638/molecular-determinants-and-signaling-effects-of-pka-ri%C3%AE-phase-separation
#10
JOURNAL ARTICLE
Julia C Hardy, Emily H Pool, Jessica G H Bruystens, Xin Zhou, Qingrong Li, Daojia R Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L C Choi, Ha Neul Lee, Stefan Strack, Dong Wang, Susan S Taylor, Sohum Mehta, Jin Zhang
Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins...
March 22, 2024: Molecular Cell
https://read.qxmd.com/read/38537639/the-splicing-regulators-rbm5-and-rbm10-are-subunits-of-the-u2-snrnp-engaged-with-intron-branch-sites-on-chromatin
#11
JOURNAL ARTICLE
Andrey Damianov, Chia-Ho Lin, Jeffrey Huang, Lin Zhou, Yasaman Jami-Alahmadi, Parham Peyda, James Wohlschlegel, Douglas L Black
Understanding the mechanisms of pre-mRNA splicing is limited by the technical challenges to examining spliceosomes in vivo. Here, we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of mammalian cell nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA bound with protected RNA fragments that precisely map to intronic branch sites across the transcriptome. These U2 complexes also contained the splicing regulators RBM5 and RBM10...
March 21, 2024: Molecular Cell
https://read.qxmd.com/read/38547866/eif4f-is-a-thermo-sensing-regulatory-node-in-the-translational-heat-shock-response
#12
JOURNAL ARTICLE
Christine Desroches Altamirano, Moo-Koo Kang, Mareike A Jordan, Tom Borianne, Irem Dilmen, Maren Gnädig, Alexander von Appen, Alf Honigmann, Titus M Franzmann, Simon Alberti
Heat-shocked cells prioritize the translation of heat shock (HS) mRNAs, but the underlying mechanism is unclear. We report that HS in budding yeast induces the disassembly of the eIF4F complex, where eIF4G and eIF4E assemble into translationally arrested mRNA ribonucleoprotein particles (mRNPs) and HS granules (HSGs), whereas eIF4A promotes HS translation. Using in vitro reconstitution biochemistry, we show that a conformational rearrangement of the thermo-sensing eIF4A-binding domain of eIF4G dissociates eIF4A and promotes the assembly with mRNA into HS-mRNPs, which recruit additional translation factors, including Pab1p and eIF4E, to form multi-component condensates...
March 19, 2024: Molecular Cell
https://read.qxmd.com/read/38521065/transcription-elongation-defects-link-oncogenic-sf3b1-mutations-to-targetable-alterations-in-chromatin-landscape
#13
JOURNAL ARTICLE
Prajwal C Boddu, Abhishek K Gupta, Rahul Roy, Bárbara De La Peña Avalos, Anne Olazabal-Herrero, Nils Neuenkirchen, Joshua T Zimmer, Namrata S Chandhok, Darren King, Yasuhito Nannya, Seishi Ogawa, Haifan Lin, Matthew D Simon, Eloise Dray, Gary M Kupfer, Amit Verma, Karla M Neugebauer, Manoj M Pillai
Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1...
March 18, 2024: Molecular Cell
https://read.qxmd.com/read/38521066/modularity-of-prc1-composition-and-chromatin-interaction-define-condensate-properties
#14
JOURNAL ARTICLE
Stefan Niekamp, Sharon K Marr, Theresa A Oei, Radhika Subramanian, Robert E Kingston
Polycomb repressive complexes (PRCs) play a key role in gene repression and are indispensable for proper development. Canonical PRC1 forms condensates in vitro and in cells that are proposed to contribute to the maintenance of repression. However, how chromatin and the various subunits of PRC1 contribute to condensation is largely unexplored. Using a reconstitution approach and single-molecule imaging, we demonstrate that nucleosomal arrays and PRC1 act synergistically, reducing the critical concentration required for condensation by more than 20-fold...
March 15, 2024: Molecular Cell
https://read.qxmd.com/read/38513661/h3k4me1-facilitates-promoter-enhancer-interactions-and-gene-activation-during-embryonic-stem-cell-differentiation
#15
JOURNAL ARTICLE
Naoki Kubo, Poshen B Chen, Rong Hu, Zhen Ye, Hiroyuki Sasaki, Bing Ren
Histone H3 lysine 4 mono-methylation (H3K4me1) marks poised or active enhancers. KMT2C (MLL3) and KMT2D (MLL4) catalyze H3K4me1, but their histone methyltransferase activities are largely dispensable for transcription during early embryogenesis in mammals. To better understand the role of H3K4me1 in enhancer function, we analyze dynamic enhancer-promoter (E-P) interactions and gene expression during neural differentiation of the mouse embryonic stem cells. We found that KMT2C/D catalytic activities were only required for H3K4me1 and E-P contacts at a subset of candidate enhancers, induced upon neural differentiation...
March 15, 2024: Molecular Cell
https://read.qxmd.com/read/38503286/a-kinetic-dichotomy-between-mitochondrial-and-nuclear-gene-expression-processes
#16
JOURNAL ARTICLE
Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman
Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments...
March 14, 2024: Molecular Cell
https://read.qxmd.com/read/38503285/lysosomal-damage-sensing-and-lysophagy-initiation-by-spg20-itch
#17
JOURNAL ARTICLE
Pinki Gahlot, Bojana Kravic, Giulia Rota, Johannes van den Boom, Sophie Levantovsky, Nina Schulze, Elena Maspero, Simona Polo, Christian Behrends, Hemmo Meyer
Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane...
March 14, 2024: Molecular Cell
https://read.qxmd.com/read/38521067/mitotic-chromosomes-are-self-entangled-and-disentangle-through-a-topoisomerase-ii-dependent-two-stage-exit-from-mitosis
#18
JOURNAL ARTICLE
Erica M Hildebrand, Kirill Polovnikov, Bastiaan Dekker, Yu Liu, Denis L Lafontaine, A Nicole Fox, Ying Li, Sergey V Venev, Leonid A Mirny, Job Dekker
The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase chromosomes are largely free of entanglements. Here, we use Hi-C, polymer simulations, and multi-contact 3C and find that, by contrast, mitotic chromosomes are self-entangled. We explore how a mitotic self-entangled state is converted into an unentangled interphase state during mitotic exit. Most mitotic entanglements are removed during anaphase/telophase, with remaining ones removed during early G1, in a topoisomerase-II-dependent process...
March 13, 2024: Molecular Cell
https://read.qxmd.com/read/38513662/erma-tmem94-is-a-p-type-atpase-transporter-for-mg-2-uptake-in-the-endoplasmic-reticulum
#19
JOURNAL ARTICLE
Neelanjan Vishnu, Manigandan Venkatesan, Travis R Madaris, Mridula K Venkateswaran, Kristen Stanley, Karthik Ramachandran, Adhishree Chidambaram, Abitha K Madesh, Wenli Yang, Jyotsna Nair, Melanie Narkunan, Tharani Muthukumar, Varsha Karanam, Leroy C Joseph, Amy Le, Ayodeji Osidele, M Imran Aslam, John P Morrow, May C Malicdan, Peter B Stathopulos, Muniswamy Madesh
Intracellular Mg2+ (i Mg2+ ) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major i Mg2+ compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases...
March 13, 2024: Molecular Cell
https://read.qxmd.com/read/38508183/fam86a-methylation-of-eef2-links-mrna-translation-elongation-to-tumorigenesis
#20
JOURNAL ARTICLE
Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani
eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation...
March 12, 2024: Molecular Cell
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