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Molecular Cell

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https://www.readbyqxmd.com/read/28065598/cas13b-is-a-type-vi-b-crispr-associated-rna-guided-rnase-differentially-regulated-by-accessory-proteins-csx27-and-csx28
#1
Aaron A Smargon, David B T Cox, Neena K Pyzocha, Kaijie Zheng, Ian M Slaymaker, Jonathan S Gootenberg, Omar A Abudayyeh, Patrick Essletzbichler, Sergey Shmakov, Kira S Makarova, Eugene V Koonin, Feng Zhang
CRISPR-Cas adaptive immune systems defend microbes against foreign nucleic acids via RNA-guided endonucleases. Using a computational sequence database mining approach, we identify two class 2 CRISPR-Cas systems (subtype VI-B) that lack Cas1 and Cas2 and encompass a single large effector protein, Cas13b, along with one of two previously uncharacterized associated proteins, Csx27 and Csx28. We establish that these CRISPR-Cas systems can achieve RNA interference when heterologously expressed. Through a combination of biochemical and genetic experiments, we show that Cas13b processes its own CRISPR array with short and long direct repeats, cleaves target RNA, and exhibits collateral RNase activity...
January 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28065601/initiation-of-quality-control-during-poly-a-translation-requires-site-specific-ribosome-ubiquitination
#2
Szymon Juszkiewicz, Ramanujan S Hegde
Diverse cellular stressors have been observed to trigger site-specific ubiquitination on several ribosomal proteins. However, the ubiquitin ligases, biochemical consequences, and physiologic pathways linked to these modifications are not known. Here, we show in mammalian cells that the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences. ZNF598-mediated stalling initiated the ribosome-associated quality control (RQC) pathway for degradation of nascent truncated proteins...
December 22, 2016: Molecular Cell
https://www.readbyqxmd.com/read/28065599/homology-requirements-and-competition-between-gene-conversion-and-break-induced-replication-during-double-strand-break-repair
#3
Anuja Mehta, Annette Beach, James E Haber
Saccharomyces cerevisiae mating-type switching is initiated by a double-strand break (DSB) at MATa, leaving one cut end perfectly homologous to the HMLα donor, while the second end must be processed to remove a non-homologous tail before completing repair by gene conversion (GC). When homology at the matched end is ≤150 bp, efficient repair depends on the recombination enhancer, which tethers HMLα near the DSB. Thus, homology shorter than an apparent minimum efficient processing segment can be rescued by tethering the donor near the break...
December 22, 2016: Molecular Cell
https://www.readbyqxmd.com/read/28107650/acetylation-enhances-tet2-function-in-protecting-against-abnormal-dna-methylation-during-oxidative-stress
#4
Yang W Zhang, Zhihong Wang, Wenbing Xie, Yi Cai, Limin Xia, Hariharan Easwaran, Jianjun Luo, Ray-Whay Chiu Yen, Yana Li, Stephen B Baylin
TET proteins, by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are hypothesized, but not directly shown, to protect promoter CpG islands (CGIs) against abnormal DNA methylation (DNAm) in cancer. We define such a protective role linked to DNA damage from oxidative stress (OS) known to induce this abnormality. TET2 removes aberrant DNAm during OS through interacting with DNA methyltransferases (DNMTs) in a "Yin-Yang" complex targeted to chromatin and enhanced by p300 mediated TET2 acetylation...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28107649/rpa-interacts-with-hira-and-regulates-h3-3-deposition-at-gene-regulatory-elements-in-mammalian-cells
#5
Honglian Zhang, Haiyun Gan, Zhiquan Wang, Jeong-Heon Lee, Hui Zhou, Tamas Ordog, Marc S Wold, Mats Ljungman, Zhiguo Zhang
The histone chaperone HIRA is involved in depositing histone variant H3.3 into distinct genic regions, including promoters, enhancers, and gene bodies. However, how HIRA deposits H3.3 to these regions remains elusive. Through a short hairpin RNA (shRNA) screening, we identified single-stranded DNA binding protein replication protein A (RPA) as a regulator of the deposition of newly synthesized H3.3 into chromatin. We show that RPA physically interacts with HIRA to form RPA-HIRA-H3.3 complexes, and it co-localizes with HIRA and H3...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28107648/parp-1-controls-the-adipogenic-transcriptional-program-by-parylating-c-ebp%C3%AE-and-modulating-its-transcriptional-activity
#6
Xin Luo, Keun Woo Ryu, Dae-Seok Kim, Tulip Nandu, Carlos J Medina, Rebecca Gupte, Bryan A Gibson, Raymond E Soccio, Yonghao Yu, Rana K Gupta, W Lee Kraus
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARylation has been studied extensively, few examples of definitive biological roles for site-specific PARylation have been reported. Here we show that C/EBPβ, a key pro-adipogenic transcription factor, is PARylated by PARP-1 on three amino acids in a conserved regulatory domain. PARylation at these sites inhibits C/EBPβ's DNA binding and transcriptional activities and attenuates adipogenesis in various genetic and cell-based models...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28107647/programmed-ribosomal-frameshifting-generates-a-copper-transporter-and-a-copper-chaperone-from-the-same-gene
#7
Sezen Meydan, Dorota Klepacki, Subbulakshmi Karthikeyan, Tõnu Margus, Paul Thomas, John E Jones, Yousuf Khan, Joseph Briggs, Jonathan D Dinman, Nora Vázquez-Laslop, Alexander S Mankin
Metal efflux pumps maintain ion homeostasis in the cell. The functions of the transporters are often supported by chaperone proteins, which scavenge the metal ions from the cytoplasm. Although the copper ion transporter CopA has been known in Escherichia coli, no gene for its chaperone had been identified. We show that the CopA chaperone is expressed in E. coli from the same gene that encodes the transporter. Some ribosomes translating copA undergo programmed frameshifting, terminate translation in the -1 frame, and generate the 70 aa-long polypeptide CopA(Z), which helps cells survive toxic copper concentrations...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28107646/an-orphan-riboswitch-unveils-guanidine-regulation-in-bacteria
#8
Wendy W K Mok, Mark P Brynildsen
In this issue, Nelson and colleagues (2017) determined that guanidine, the prevalent protein denaturant, is the long-lost ligand sensed by the ykkC class of riboswitches, and identified that members of its regulon are involved in guanidine detoxification and export.
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28107645/a-cu-rious-ribosomal-profiling-pattern-leads-to-the-discovery-of-ribosomal-frameshifting-in-the-synthesis-of-a-copper-chaperone
#9
John F Atkins, Gary Loughran, Pavel V Baranov
In many bacteria, separate genes encode a copper binding chaperone and a copper efflux pump, but in some the chaperone encoding gene has been elusive. In this issue of Molecular Cell, Meydan et al. (2017) report that ribosomes translating the ORF that encodes the copper pump frequently frameshift and terminate to produce the copper chaperone.
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28089683/coupling-of-homologous-recombination-and-the-checkpoint-by-atr
#10
Rémi Buisson, Joshi Niraj, Amélie Rodrigue, Chu Kwen Ho, Johannes Kreuzer, Tzeh Keong Foo, Emilie J-L Hardy, Graham Dellaire, Wilhelm Haas, Bing Xia, Jean-Yves Masson, Lee Zou
ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28065600/lysyl-oxidase-3-is-a-dual-specificity-enzyme-involved-in-stat3-deacetylation-and-deacetylimination-modulation
#11
Li Ma, Chao Huang, Xiong-Jun Wang, Dazhuan Eric Xin, Li-Shun Wang, Quanli C Zou, Ya-Nan S Zhang, Min-Dian Tan, Yu-Mei Wang, Ting C Zhao, Devasis Chatterjee, Rachel A Altura, Chuangui Wang, Yan S Xu, Jing-Hua Yang, Yong-Sheng Fan, Bao-Hui Han, Jianmin Si, Xiaoren Zhang, Jinke Cheng, Zhijie Chang, Y Eugene Chin
In mammalian cells, histone deacetylase (HDAC) and Sirtuin (SIRT) are two families responsible for removing acetyl groups from acetylated proteins. Here, we describe protein deacetylation coupled with deacetylimination as a function of lysyl oxidase (LOX) family members. LOX-like 3 (Loxl3) associates with Stat3 in the nucleus to deacetylate and deacetyliminate Stat3 on multiple acetyl-lysine sites. Surprisingly, Loxl3 N-terminal scavenger receptor cysteine-rich (SRCR) repeats, rather than the C-terminal oxidase catalytic domain, represent the major deacetylase/deacetyliminase activity...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28065597/a-global-analysis-of-the-receptor-tyrosine-kinase-protein-phosphatase-interactome
#12
Zhong Yao, Katelyn Darowski, Nicole St-Denis, Victoria Wong, Fabian Offensperger, Annabel Villedieu, Shahreen Amin, Ramy Malty, Hiroyuki Aoki, Hongbo Guo, Yang Xu, Caterina Iorio, Max Kotlyar, Andrew Emili, Igor Jurisica, Benjamin G Neel, Mohan Babu, Anne-Claude Gingras, Igor Stagljar
Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human RTKs and phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of previously unidentified interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTPs) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28065596/a-strategy-to-combine-sample-multiplexing-with-targeted-proteomics-assays-for-high-throughput-protein-signature-characterization
#13
Brian K Erickson, Christopher M Rose, Craig R Braun, Alison R Erickson, Jeffrey Knott, Graeme C McAlister, Martin Wühr, Joao A Paulo, Robert A Everley, Steven P Gygi
Targeted mass spectrometry assays for protein quantitation monitor peptide surrogates, which are easily multiplexed to target many peptides in a single assay. However, these assays have generally not taken advantage of sample multiplexing, which allows up to ten analyses to occur in parallel. We present a two-dimensional multiplexing workflow that utilizes synthetic peptides for each protein to prompt the simultaneous quantification of >100 peptides from up to ten mixed sample conditions. We demonstrate that targeted analysis of unfractionated lysates (2 hr) accurately reproduces the quantification of fractionated lysates (72 hr analysis) while obviating the need for peptide detection prior to quantification...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28017591/a-dual-inhibitory-mechanism-sufficient-to-maintain-cell-cycle-restricted-cenp-a-assembly
#14
Ana Stankovic, Lucie Y Guo, João F Mata, Dani L Bodor, Xing-Jun Cao, Aaron O Bailey, Jeffrey Shabanowitz, Donald F Hunt, Benjamin A Garcia, Ben E Black, Lars E T Jansen
Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27989441/autonomous-metabolic-oscillations-robustly-gate-the-early-and-late-cell-cycle
#15
Alexandros Papagiannakis, Bastian Niebel, Ernst C Wit, Matthias Heinemann
Eukaryotic cell division is known to be controlled by the cyclin/cyclin dependent kinase (CDK) machinery. However, eukaryotes have evolved prior to CDKs, and cells can divide in the absence of major cyclin/CDK components. We hypothesized that an autonomous metabolic oscillator provides dynamic triggers for cell-cycle initiation and progression. Using microfluidics, cell-cycle reporters, and single-cell metabolite measurements, we found that metabolism of budding yeast is a CDK-independent oscillator that oscillates across different growth conditions, both in synchrony with and also in the absence of the cell cycle...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27989440/metabolism-of-free-guanidine-in-bacteria-is-regulated-by-a-widespread-riboswitch-class
#16
James W Nelson, Ruben M Atilho, Madeline E Sherlock, Randy B Stockbridge, Ronald R Breaker
The guanidyl moiety is a component of fundamental metabolites, including the amino acid arginine, the energy carrier creatine, and the nucleobase guanine. Curiously, reports regarding the importance of free guanidine in biology are sparse, and no biological receptors that specifically recognize this compound have been previously identified. We report that many members of the ykkC motif RNA, the longest unresolved riboswitch candidate, naturally sense and respond to guanidine. This RNA is found throughout much of the bacterial domain of life, where it commonly controls the expression of proteins annotated as urea carboxylases and multidrug efflux pumps...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27989439/c2c1-sgrna-complex-structure-reveals-rna-guided-dna-cleavage-mechanism
#17
Liang Liu, Peng Chen, Min Wang, Xueyan Li, Jiuyu Wang, Maolu Yin, Yanli Wang
C2c1 is a type V-B CRISPR-Cas system dual-RNA-guided DNA endonuclease. Here, we report the crystal structure of Alicyclobacillus acidoterrestris C2c1 in complex with a chimeric single-molecule guide RNA (sgRNA). AacC2c1 exhibits a bi-lobed architecture consisting of a REC and NUC lobe. The sgRNA scaffold forms a tetra-helical structure, distinct from previous predictions. The crRNA is located in the central channel of C2c1, and the tracrRNA resides in an external surface groove. Although AacC2c1 lacks a PAM-interacting domain, our analysis revealed that the PAM duplex has a similar binding position found in Cpf1...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27986371/mechanism-of-ubiquitination-and-deubiquitination-in-the-fanconi-anemia-pathway
#18
Sylvie van Twest, Vincent J Murphy, Charlotte Hodson, Winnie Tan, Paolo Swuec, Julienne J O'Rourke, Jörg Heierhorst, Wayne Crismani, Andrew J Deans
Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28061334/arginine-methylation-the-coming-of-age
#19
REVIEW
Roméo S Blanc, Stéphane Richard
Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription and playing key roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. Recently, a wealth of studies using transgenic mouse models and selective PRMT inhibitors helped define physiological roles for protein arginine methyltransferases (PRMTs) linking them to diseases such as cancer and metabolic, neurodegenerative, and muscular disorders...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28061333/thinking-outside-the-cell-replicating-replication-in%C3%A2-vitro
#20
Rhiannon R Aguilar, Jessica K Tyler
Benchmark studies by Yeeles et al. (2017), Kurat et al. (2017), and Devbhandari et al. (2017) have reconstituted rapid and regulated budding yeast DNA replication on naked and chromatinized templates in vitro, providing key insights into this fundamentally important process.
January 5, 2017: Molecular Cell
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