Molecular Cell

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A Mammalian Pre-mRNA 5′ End Capping Quality Control Mechanism and an Unexpected Link of Capping to Pre-mRNA Processing

Xinfu Jiao, Jeong Ho Chang, Turgay Kilic, Liang Tong, more

Molecular Cell > 2013 > 50 > 1 > 104-115

Recently, we reported that two homologous yeast proteins, Rai1 and Dxo1, function in a quality control mechanism to clear cells of incompletely 5′ end-capped messenger RNAs (mRNAs). Here, we report that their mammalian homolog, Dom3Z (referred to as DXO), possesses pyrophosphohydrolase, decapping, and 5′-to-3′ exoribonuclease activities. Surprisingly, we found that DXO preferentially degrades defectively...

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STING Recognition of Cytoplasmic DNA Instigates Cellular Defense

Takayuki Abe, Ai Harashima, Tianli Xia, Hiroyasu Konno, more

Molecular Cell > 2013 > 50 > 1 > 5-15

How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related...

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DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

Adam N. Yadon, Badri Nath Singh, Michael Hampsey, Toshio Tsukiyama

Molecular Cell > 2013 > 50 > 1 > 93-103

ATP-dependent chromatin remodeling enzymes are highly abundant and play pivotal roles regulating DNA-dependent processes. The mechanisms by which they are targeted to specific loci have not been well understood on a genome-wide scale. Here, we present evidence that a major targeting mechanism for the Isw2 chromatin remodeling enzyme to specific genomic loci is through sequence-specific transcription...

article

Discovery of Functional Toxin/Antitoxin Systems in Bacteria by Shotgun Cloning

Hila Sberro, Azita Leavitt, Ruth Kiro, Eugene Koh, more

Molecular Cell > 2013 > 50 > 1 > 136-148

Toxin-antitoxin (TA) modules, composed of a toxic protein and a counteracting antitoxin, play important roles in bacterial physiology. We examined the experimental insertion of 1.5 million genes from 388 microbial genomes into an Escherichia coli host using more than 8.5 million random clones. This revealed hundreds of genes (toxins) that could only be cloned when the neighboring gene (antitoxin)...

article

Class IA PI3K p110β Subunit Promotes Autophagy through Rab5 Small GTPase in Response to Growth Factor Limitation

Zhixun Dou, Ji-An Pan, Hashem A. Dbouk, Lisa M. Ballou, more

Molecular Cell > 2013 > 50 > 1 > 29-42

Autophagy is an evolutionarily conserved membrane trafficking process. Induction of autophagy in response to nutrient limitation or cellular stress occurs by similar mechanisms in organisms from yeast to mammals. Unlike yeast, metazoan cells rely more on growth factor signaling for a wide variety of cellular activities including nutrient uptake. How growth factor availability regulates autophagy is...

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Judge, Jury, and Executioner: DXO Functions as a Decapping Enzyme and Exoribonuclease in Pre-mRNA Quality Control

Jeffrey S. Mugridge, John D. Gross

Molecular Cell > 2013 > 50 > 1 > 2-4

In this issue of Molecular Cell, Jiao et al. (2013) describe the mammalian enzyme DXO, which has pyrophosphohydrolase, decapping, and 5′-3′ exoribonuclease activity and functions as an important checkpoint in cotranscriptional capping of RNA polymerase II (Pol II) pre-mRNA transcripts.

article

How Do Cells Sense Foreign DNA? A New Outlook on the Function of STING

David Wallach, Andrew Kovalenko

Molecular Cell > 2013 > 50 > 1 > 1-2

STING, a protein mediating signaling activation by cytosolic DNA and known to act downstream of DNA sensor proteins, is shown also to bind DNA directly, raising the need to clarify the relative contributions of these distinct binding modes to DNA sensing.

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ZKSCAN3 Is a Master Transcriptional Repressor of Autophagy

Santosh Chauhan, Jinesh G. Goodwin, Swati Chauhan, Ganiraju Manyam, more

Molecular Cell > 2013 > 50 > 1 > 16-28

Autophagy constitutes a major cell-protective mechanism that eliminates damaged components and maintains energy homeostasis via recycling nutrients under normal/stressed conditions. Although the core components of autophagy have been well studied, regulation of autophagy at the transcriptional level is poorly understood. Herein, we establish ZKSCAN3, a zinc finger family DNA-binding protein, as a...

article

Hsp90 Regulates Nongenetic Variation in Response to Environmental Stress

Yu-Ying Hsieh, Po-Hsiang Hung, Jun-Yi Leu

Molecular Cell > 2013 > 50 > 1 > 82-92

Nongenetic cell-to-cell variability often plays an important role for the survival of a clonal population in the face of fluctuating environments. However, the underlying mechanisms regulating such nongenetic heterogeneity remain elusive in most organisms. We report here that a clonal yeast population exhibits morphological heterogeneity when the level of Hsp90, a molecular chaperone, is reduced....

article

Splicing-Factor Oncoprotein SRSF1 Stabilizes p53 via RPL5 and Induces Cellular Senescence

Oliver I. Fregoso, Shipra Das, Martin Akerman, Adrian R. Krainer

Molecular Cell > 2013 > 50 > 1 > 56-66

Splicing and translation are highly regulated steps of gene expression. Altered expression of proteins involved in these processes can be deleterious. Therefore, the cell has many safeguards against such misregulation. We report that the oncogenic splicing factor SRSF1, which is overexpressed in many cancers, stabilizes the tumor suppressor protein p53 by abrogating its MDM2-dependent proteasomal...

article

MEK1 Is Required for PTEN Membrane Recruitment, AKT Regulation, and the Maintenance of Peripheral Tolerance

Katarina Zmajkovicova, Veronika Jesenberger, Federica Catalanotti, Christian Baumgartner, more

Molecular Cell > 2013 > 50 > 1 > 43-55

The Raf/MEK/ERK and PI3K/Akt pathways are prominent effectors of oncogenic Ras. These pathways negatively regulate each other, but the mechanism involved is incompletely understood. We now identify MEK1 as an essential regulator of lipid/protein phosphatase PTEN, through which it controls phosphatidylinositol-3-phosphate accumulation and AKT signaling. MEK1 ablation stabilizes AKT activation and,...

article

An Ancient Transcription Factor Initiates the Burst of piRNA Production during Early Meiosis in Mouse Testes

Xin Zhiguo Li, Christian K. Roy, Xianjun Dong, Ewelina Bolcun-Filas, more

Molecular Cell > 2013 > 50 > 1 > 67-81

Animal germ cells produce PIWI-interacting RNAs (piRNAs), small silencing RNAs that suppress transposons and enable gamete maturation. Mammalian transposon-silencing piRNAs accumulate early in spermatogenesis, whereas pachytene piRNAs are produced later during postnatal spermatogenesis and account for >95% of all piRNAs in the adult mouse testis. Mutants defective for pachytene piRNA pathway proteins...

article

Evidence against a Role for β-Arrestin1 in STAT1 Dephosphorylation and the Inhibition of Interferon-γ Signaling

Christin Pelzel, Andreas Begitt, Nikola Wenta, Uwe Vinkemeier

Molecular Cell > 2013 > 50 > 1 > 149-156

Signal transducer and activator of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-γ (IFNγ) stimulation, which results in the expression of genes with antiproliferative and immunomodulatory functions. The inactivation of STAT1 occurs through tyrosine dephosphorylation by the tyrosine phosphatase TC45. It was proposed that recruitment of TC45 required the direct interaction...

article

Quantitative, Genome-Wide Analysis of Eukaryotic Replication Initiation and Termination

Sean R. McGuffee, Duncan J. Smith, Iestyn Whitehouse

Molecular Cell > 2013 > 50 > 1 > 123-135

Many fundamental aspects of DNA replication, such as the exact locations where DNA synthesis is initiated and terminated, how frequently origins are used, and how fork progression is influenced by transcription, are poorly understood. Via the deep sequencing of Okazaki fragments, we comprehensively document replication fork directionality throughout the S. cerevisiae genome, which permits the systematic...

article

A Role for the MRN Complex in ATR Activation via TOPBP1 Recruitment

Anja M. Duursma, Robert Driscoll, Josh E. Elias, Karlene A. Cimprich

Molecular Cell > 2013 > 50 > 1 > 116-122

The MRN (MRE11-RAD50-NBS1) complex has been implicated in many aspects of the DNA damage response. It has key roles in sensing and processing DNA double-strand breaks, as well as in activation of ATM (ataxia telangiectasia mutated). We reveal a function for MRN in ATR (ATM- and RAD3-related) activation by using defined ATR-activating DNA structures in Xenopus egg extracts. Strikingly, we demonstrate...

article

C. elegans DPY-19 Is a C-Mannosyltransferase Glycosylating Thrombospondin Repeats

Falk F.R. Buettner, Angel Ashikov, Birgit Tiemann, Ludwig Lehle, more

Molecular Cell > 2013 > 50 > 2 > 295-302

Among the different types of protein glycosylation, C-mannosylation of tryptophan residues stands out because of the unique linkage formed between sugar and protein. Instead of the typical O- or N-glycosidic linkage, a C-C bond is used for attachment of a single mannose. C-mannose is characteristically found in thrombospondin type 1 repeats and in the WSXWS motif of type I cytokine receptors. The...

article

Neurodegeneration-Associated Protein Fragments as Short-Lived Substrates of the N-End Rule Pathway

Christopher S. Brower, Konstantin I. Piatkov, Alexander Varshavsky

Molecular Cell > 2013 > 50 > 2 > 161-171

Protein aggregates are a common feature of neurodegenerative syndromes. Specific protein fragments were found to be aggregated in disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Here, we show that the natural C-terminal fragments of Tau, TDP43, and α-synuclein are short-lived substrates of the Arg/N-end rule pathway, a processive proteolytic system...

article

The Decapping Scavenger Enzyme DCS-1 Controls MicroRNA Levels in Caenorhabditis elegans

Gabriel D. Bossé, Stefan Rüegger, Maria C. Ow, Alejandro Vasquez-Rifo, more

Molecular Cell > 2013 > 50 > 2 > 281-287

In metazoans, microRNAs play a critical role in the posttranscriptional regulation of genes required for cell proliferation and differentiation. MicroRNAs themselves are regulated by a multitude of mechanisms influencing their transcription and posttranscriptional maturation. However, there is only sparse knowledge on pathways regulating the mature, functional form of microRNA. Here, we uncover the...

article

Monitoring Homology Search during DNA Double-Strand Break Repair In Vivo

Jörg Renkawitz, Claudio A. Lademann, Marian Kalocsay, Stefan Jentsch

Molecular Cell > 2013 > 50 > 2 > 261-272

Homologous recombination (HR) is crucial for genetic exchange and accurate repair of DNA double-strand breaks and is pivotal for genome integrity. HR uses homologous sequences for repair, but how homology search, the exploration of the genome for homologous DNA sequences, is conducted in the nucleus remains poorly understood. Here, we use time-resolved chromatin immunoprecipitations of repair proteins...

article

Two Antagonistic Clock-Regulated Histidine Kinases Time the Activation of Circadian Gene Expression

Andrian Gutu, Erin K. O’Shea

Molecular Cell > 2013 > 50 > 2 > 288-294

The cyanobacterial circadian pacemaker consists of a three-protein clock—KaiA, KaiB, and KaiC—that generates oscillations in the phosphorylation state of KaiC. Here we investigate how temporal information encoded in KaiC phosphorylation is transduced to RpaA, a transcription factor required for circadian gene expression. We show that phosphorylation of RpaA is regulated by two antagonistic histidine...

INFONA - science communication portal

Molecular Cell

A Mammalian Pre-mRNA 5′ End Capping Quality Control Mechanism and an Unexpected Link of Capping to Pre-mRNA Processing

STING Recognition of Cytoplasmic DNA Instigates Cellular Defense

DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

Discovery of Functional Toxin/Antitoxin Systems in Bacteria by Shotgun Cloning

Class IA PI3K p110β Subunit Promotes Autophagy through Rab5 Small GTPase in Response to Growth Factor Limitation

Judge, Jury, and Executioner: DXO Functions as a Decapping Enzyme and Exoribonuclease in Pre-mRNA Quality Control

How Do Cells Sense Foreign DNA? A New Outlook on the Function of STING

ZKSCAN3 Is a Master Transcriptional Repressor of Autophagy

Hsp90 Regulates Nongenetic Variation in Response to Environmental Stress

Splicing-Factor Oncoprotein SRSF1 Stabilizes p53 via RPL5 and Induces Cellular Senescence

MEK1 Is Required for PTEN Membrane Recruitment, AKT Regulation, and the Maintenance of Peripheral Tolerance

An Ancient Transcription Factor Initiates the Burst of piRNA Production during Early Meiosis in Mouse Testes

Evidence against a Role for β-Arrestin1 in STAT1 Dephosphorylation and the Inhibition of Interferon-γ Signaling

Quantitative, Genome-Wide Analysis of Eukaryotic Replication Initiation and Termination

A Role for the MRN Complex in ATR Activation via TOPBP1 Recruitment

C. elegans DPY-19 Is a C-Mannosyltransferase Glycosylating Thrombospondin Repeats

Neurodegeneration-Associated Protein Fragments as Short-Lived Substrates of the N-End Rule Pathway

The Decapping Scavenger Enzyme DCS-1 Controls MicroRNA Levels in Caenorhabditis elegans

Monitoring Homology Search during DNA Double-Strand Break Repair In Vivo

Two Antagonistic Clock-Regulated Histidine Kinases Time the Activation of Circadian Gene Expression

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