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Molecular Cell

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https://www.readbyqxmd.com/read/28506461/mk2-phosphorylates-ripk1-to-prevent-tnf-induced-cell-death
#1
Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, Rebecca Wilson, Tencho Tenev, Lucie Laurien, Chun Kim, Kunzah Jamal, Sidonie Wicky John, Gianmaria Liccardi, Diep Chau, James M Murphy, Gabriela Brumatti, Rebecca Feltham, Manolis Pasparakis, John Silke, Pascal Meier
TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis...
May 10, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525745/conditional-switch-between-frameshifting-regimes-upon-translation-of-dnax-mrna
#2
Neva Caliskan, Ingo Wohlgemuth, Natalia Korniy, Michael Pearson, Frank Peske, Marina V Rodnina
Ribosome frameshifting during translation of bacterial dnaX can proceed via different routes, generating a variety of distinct polypeptides. Using kinetic experiments, we show that -1 frameshifting predominantly occurs during translocation of two tRNAs bound to the slippery sequence codons. This pathway depends on a stem-loop mRNA structure downstream of the slippery sequence and operates when aminoacyl-tRNAs are abundant. However, when aminoacyl-tRNAs are in short supply, the ribosome switches to an alternative frameshifting pathway that is independent of a stem-loop...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525744/ctf4-prevents-genome-rearrangements-by-suppressing-dna-double-strand-break-formation-and-its-end-resection-at-arrested-replication-forks
#3
Mariko Sasaki, Takehiko Kobayashi
Arrested replication forks lead to DNA double-strand breaks (DSBs), which are a major source of genome rearrangements. Yet DSB repair in the context of broken forks remains poorly understood. Here we demonstrate that DSBs that are formed at arrested forks in the budding yeast ribosomal RNA gene (rDNA) locus are normally repaired by pathways dependent on the Mre11-Rad50-Xrs2 complex but independent of HR. HR is also dispensable for DSB repair at stalled forks at tRNA genes. In contrast, in cells lacking the core replisome component Ctf4, DSBs are formed more frequently, and these DSBs undergo end resection and HR-mediated repair that is prone to rDNA hyper-amplification; this highlights Ctf4 as a key regulator of DSB end resection at arrested forks...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525743/bromodomain-protein-brd4-is-a-transcriptional-repressor-of-autophagy-and-lysosomal-function
#4
Jun-Ichi Sakamaki, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O'Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Maria New, Tim Van Acker, Sharon A Tooze, Scott W Lowe, Ivan Dikic, Kevin M Ryan
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525742/ubiquitin-modification-by-the-e3-ligase-adp-ribosyltransferase-dtx3l-parp9
#5
Chun-Song Yang, Kasey Jividen, Adam Spencer, Natalia Dworak, Li Ni, Luke T Oostdyk, Mandovi Chatterjee, Beata Kuśmider, Brian Reon, Mahmut Parlak, Vera Gorbunova, Tarek Abbas, Erin Jeffery, Nicholas E Sherman, Bryce M Paschal
ADP-ribosylation of proteins is emerging as an important regulatory mechanism. Depending on the family member, ADP-ribosyltransferases either conjugate a single ADP-ribose to a target or generate ADP-ribose chains. Here we characterize Parp9, a mono-ADP-ribosyltransferase reported to be enzymatically inactive. Parp9 undergoes heterodimerization with Dtx3L, a histone E3 ligase involved in DNA damage repair. We show that the Dtx3L/Parp9 heterodimer mediates NAD(+)-dependent mono-ADP-ribosylation of ubiquitin, exclusively in the context of ubiquitin processing by E1 and E2 enzymes...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525741/in%C3%A2-vivo-ubiquitin-linkage-type-analysis-reveals-that-the-cdc48-rad23-dsk2-axis-contributes-to-k48-linked-chain-specificity-of-the-proteasome
#6
Hikaru Tsuchiya, Fumiaki Ohtake, Naoko Arai, Ai Kaiho, Sayaka Yasuda, Keiji Tanaka, Yasushi Saeki
Ubiquitin-binding domain (UBD) proteins regulate numerous cellular processes, but their specificities toward ubiquitin chain types in cells remain obscure. Here, we perform a quantitative proteomic analysis of ubiquitin linkage-type selectivity of 14 UBD proteins and the proteasome in yeast. We find that K48-linked chains are directed to proteasomal degradation through selectivity of the Cdc48 cofactor Npl4. Mutating Cdc48 results in decreased selectivity, and lacking Rad23/Dsk2 abolishes interactions between ubiquitylated substrates and the proteasome...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525740/rnf8-and-ube2s-dependent-ubiquitin-lysine-11-linkage-modification-in-response-to-dna-damage
#7
Atanu Paul, Bin Wang
Ubiquitin modification of proteins plays pivotal roles in the cellular response to DNA damage. Given the complexity of ubiquitin conjugation due to the formation of poly-conjugates of different linkages, functional roles of linkage-specific ubiquitin modification at DNA damage sites are largely unclear. We identify that Lys11-linkage ubiquitin modification occurs at DNA damage sites in an ATM-dependent manner, and ubiquitin-modifying enzymes, including Ube2S E2-conjugating enzyme and RNF8 E3 ligase, are responsible for the assembly of Lys11-linkage conjugates on damaged chromatin, including histone H2A/H2AX...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525739/genome-organization-cohesin-on-the-move
#8
Judita Richterova, Barbora Huraiova, Juraj Gregan
Folding of mammalian genomes into spatial domains is thought to depend on cohesin and CTCF proteins. Busslinger et al. (2017) reveal that transcription moves cohesin along DNA to CTCF-binding sites, providing insights into how cohesin and CTCF mediate chromosomal interactions by formation of chromatin loops.
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525738/synthetic-genomics-rewriting-the-genome-chromosome-by-chromosome
#9
Almer van der Sloot, Mike Tyers
The Synthetic Yeast Genome Project (Sc2.0) consortium has recently published a collection of seven reports on the design, assembly, and in vivo characterization of five entirely synthetic yeast chromosomes that set the stage for de novo construction of synthetic custom-engineered eukaryotes.
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525737/correlation-does-not-imply-causation-histone-methyltransferases-but-not-histone-methylation-set-the-stage-for-enhancer-activation
#10
Tim Pollex, Eileen E M Furlong
Although H3K4me1 is a pervasive "mark" of enhancers, its functional requirement for enhancer activity remains unclear. In this issue of Molecular Cell, Dorighi et al. (2017) show that in some contexts, the methyltransferase complex, rather than the H3K4me1 mark, is required for gene expression.
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525736/a-flick-of-the-tail-keeps-the-circadian-clock-in-line
#11
Rajesh Narasimamurthy, David M Virshup
Circadian clocks signal and adapt to an ever-changing world by juggling a panoply of transcriptional and post-translational modifications. In this issue of Molecular Cell, Gustafson et al. (2017) report an additional requirement for accurate timekeeping, a cis/trans conformational flicker in the transcriptional activation domain of the core clock protein BMAL1.
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28506463/rna-pol-ii-dynamics-modulate-co-transcriptional-chromatin-modification-ctd-phosphorylation-and-transcriptional-direction
#12
Nova Fong, Tassa Saldi, Ryan M Sheridan, Michael A Cortazar, David L Bentley
Eukaryotic genes are marked by conserved post-translational modifications on the RNA pol II C-terminal domain (CTD) and the chromatin template. How the 5'-3' profiles of these marks are established is poorly understood. Using pol II mutants in human cells, we found that slow transcription repositioned specific co-transcriptionally deposited chromatin modifications; histone H3 lysine 36 trimethyl (H3K36me3) shifted within genes toward 5' ends, and histone H3 lysine 4 dimethyl (H3K4me2) extended farther upstream of start sites...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28506462/a-slow-conformational-switch-in-the-bmal1-transactivation-domain-modulates-circadian-rhythms
#13
Chelsea L Gustafson, Nicole C Parsley, Hande Asimgil, Hsiau-Wei Lee, Christopher Ahlbach, Alicia K Michael, Haiyan Xu, Owen L Williams, Tara L Davis, Andrew C Liu, Carrie L Partch
The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28506460/mechanisms-of-ubiquitin-nucleosome-recognition-and-regulation-of-53bp1-chromatin-recruitment-by-rnf168-169-and-rad18
#14
Qi Hu, Maria Victoria Botuyan, Gaofeng Cui, Debiao Zhao, Georges Mer
The protein 53BP1 plays a central regulatory role in DNA double-strand break repair. 53BP1 relocates to chromatin by recognizing RNF168-mediated mono-ubiquitylation of histone H2A Lys15 in the nucleosome core particle dimethylated at histone H4 Lys20 (NCP-ubme). 53BP1 relocation is terminated by ubiquitin ligases RNF169 and RAD18 via unknown mechanisms. Using nuclear magnetic resonance (NMR) spectroscopy and biochemistry, we show that RNF169 bridges ubiquitin and histone surfaces, stabilizing a pre-existing ubiquitin orientation in NCP-ubme to form a high-affinity complex...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#15
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475875/dynamic-rewiring-of-promoter-anchored-chromatin-loops-during-adipocyte-differentiation
#16
Rasmus Siersbæk, Jesper Grud Skat Madsen, Biola Maria Javierre, Ronni Nielsen, Emilie Kristine Bagge, Jonathan Cairns, Steven William Wingett, Sofie Traynor, Mikhail Spivakov, Peter Fraser, Susanne Mandrup
Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr after inducing differentiation of 3T3-L1 preadipocytes. The establishment of new promoter-enhancer loops is tightly coupled to activation of poised (histone H3 lysine 4 mono- and dimethylated) enhancers, as evidenced by the acquisition of histone H3 lysine 27 acetylation and the binding of MED1, SMC1, and P300 proteins to these regions, as well as to activation of target genes...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475874/unprotected-replication-forks-are-converted-into-mitotic-sister-chromatid-bridges
#17
Anissia Ait Saada, Ana Teixeira-Silva, Ismail Iraqui, Audrey Costes, Julien Hardy, Giulia Paoletti, Karine Fréon, Sarah A E Lambert
Replication stress and mitotic abnormalities are key features of cancer cells. Temporarily paused forks are stabilized by the intra-S phase checkpoint and protected by the association of Rad51, which prevents Mre11-dependent resection. However, if a fork becomes dysfunctional and cannot resume, this terminally arrested fork is rescued by a converging fork to avoid unreplicated parental DNA during mitosis. Alternatively, dysfunctional forks are restarted by homologous recombination. Using fission yeast, we report that Rad52 and the DNA binding activity of Rad51, but not its strand-exchange activity, act to protect terminally arrested forks from unrestrained Exo1-nucleolytic activity...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475873/structure-and-dynamics-of-a-197%C3%A2-bp-nucleosome-in-complex-with-linker-histone-h1
#18
Jan Bednar, Isabel Garcia-Saez, Ramachandran Boopathi, Amber R Cutter, Gabor Papai, Anna Reymer, Sajad H Syed, Imtiaz Nisar Lone, Ognyan Tonchev, Corinne Crucifix, Hervé Menoni, Christophe Papin, Dimitrios A Skoufias, Hitoshi Kurumizaka, Richard Lavery, Ali Hamiche, Jeffrey J Hayes, Patrick Schultz, Dimitar Angelov, Carlo Petosa, Stefan Dimitrov
Linker histones associate with nucleosomes to promote the formation of higher-order chromatin structure, but the underlying molecular details are unclear. We investigated the structure of a 197 bp nucleosome bearing symmetric 25 bp linker DNA arms in complex with vertebrate linker histone H1. We determined electron cryo-microscopy (cryo-EM) and crystal structures of unbound and H1-bound nucleosomes and validated these structures by site-directed protein cross-linking and hydroxyl radical footprinting experiments...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475872/rna-targeting-by-functionally-orthogonal-type-vi-a-crispr-cas-enzymes
#19
Alexandra East-Seletsky, Mitchell R O'Connell, David Burstein, Gavin J Knott, Jennifer A Doudna
CRISPR adaptive immunity pathways protect prokaryotic cells against foreign nucleic acids using CRISPR RNA (crRNA)-guided nucleases. In type VI-A CRISPR-Cas systems, the signature protein Cas13a (formerly C2c2) contains two separate ribonuclease activities that catalyze crRNA maturation and ssRNA degradation. The Cas13a protein family occurs across different bacterial phyla and varies widely in both protein sequence and corresponding crRNA sequence conservation. Although grouped phylogenetically together, we show that the Cas13a enzyme family comprises two distinct functional groups that recognize orthogonal sets of crRNAs and possess different ssRNA cleavage specificities...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475871/aging-triggers-cytoplasmic-depletion-and-nuclear-translocation-of-the-e3-ligase-mahogunin-a%C3%A2-function-for-ubiquitin-in-neuronal-survival
#20
Stefano Benvegnù, María Inés Mateo, Ernest Palomer, Jerónimo Jurado-Arjona, Carlos G Dotti
A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1...
May 4, 2017: Molecular Cell
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