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Clk post-transcriptional control denoises circadian transcription both temporally and spatially
CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. Here, the authors show that Clk mRNA is regulated by miRNA bantam, and deletion of bantambinding site leads to stochastic CLK-driven transcription and development of the circadian neurons.
- Immanuel Lerner
- , Osnat Bartok
- & Sebastian Kadener
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Article
| Open AccessDynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation
Polypeptide GalNAc-transferases decorate proteins with dense arrays of O-glycans, which in the case of mucins are essential for their barrier functions. Here the authors present comprehensive structural studies that shed light on the molecular attributes that allow GalNAc-T2 to efficiently carry out dense O-glycosylation.
- Erandi Lira-Navarrete
- , Matilde de las Rivas
- & Ramon Hurtado-Guerrero
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| Open AccessAcetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer
Folate plays an essential role in dividing cells and is regulated by methionine adenosyltransferase (MAT), where a switch from MAT Iα to MAT IIα expression seems to promote liver cancer progression. Here the authors demonstrate that MAT IIα stability is regulated by acetylation and this regulation is important for tumour growth.
- Hong-Bin Yang
- , Ying-Ying Xu
- & Qun-Ying Lei
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dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes
dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here the authors report that dDsk2 regulates RNA polymerase II pausing by preventing H2Bub1 deubiquitylation, suggesting a nonproteolytic function of dDsk2.
- Roman Kessler
- , Johan Tisserand
- & Fernando Azorín
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| Open AccessUbiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization
The relaying of Wnt signals to the cytoplasm requires the formation of signalosomes through the reversible polymerization of Dishevelled (Dvl). Here the authors establish the functional consequences of ubiquitination of the Dvl DIX domain and identify deubiquitinases predicted to promote Dvl polymerization.
- Julia Madrzak
- , Marc Fiedler
- & Jason W. Chin
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DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis
DNA methyltransferase1 (DNMT1) plays a key role in stem cell and progenitor cell maintenance in mammalian epithelium tissues. Here the authors uncover a role for DNMT1 in the regulation of stem/progenitor cells in normal and tumorigenic mouse mammary gland.
- Rajneesh Pathania
- , Sabarish Ramachandran
- & Muthusamy Thangaraju
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ATM kinase sustains HER2 tumorigenicity in breast cancer
ATM is a tumour suppressor activated in response to DNA damage. Here, the authors unveil a new tumour-promoting role for ATM in HER2-driven breast cancers, and show that ATM stimulates the interaction between HER2 and HSP90, therefore preventing HER2 from degradation.
- Venturina Stagni
- , Isabella Manni
- & Daniela Barilà
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| Open AccessComprehensive identification of arginine methylation in primary T cells reveals regulatory roles in cell signalling
Arginine methylation is an important regulatory post-translational modification. Here, the authors present a new SILAC-based method—iMethyl-SILAC—that allows unambiguous identification of arginine-methylated peptide pairs by mass spectrometry and apply it to greatly expand the known T-cell arginine methylome.
- Vincent Geoghegan
- , Ailan Guo
- & Oreste Acuto
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| Open AccessLarge-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics
Measuring phosphorylation stoichiometry on a proteomic scale remains a challenge. Tsai et al. develop a technique to measure the basal level of phosphorylation stoichiometry in a single human phosphoproteome and identify molecular changes associated with gefitinib resistance in lung cancer cells.
- Chia-Feng Tsai
- , Yi-Ting Wang
- & Yu-Ju Chen
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ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells
How the magnitude of the response is regulated in different T-cell memory subsets remains poorly understood. Here the authors show that miR-181 lowers the threshold of Th17 memory activation via sustained Erk phosphorylation, while Erk-dependent induction of ID3 limits Th17 activity at later time.
- Federico Mele
- , Camilla Basso
- & Silvia Monticelli
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| Open AccessTranslational diffusion of hydration water correlates with functional motions in folded and intrinsically disordered proteins
Hydration water plasticizes protein structures and is essential for their biological functions, such as enzymatic catalysis. Here, the authors use neutron scattering and molecular dynamics simulations to study hydration water at the dynamical transition of folded and disordered proteins.
- Giorgio Schirò
- , Yann Fichou
- & Martin Weik
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Sumoylation controls the timing of Tup1-mediated transcriptional deactivation
Tup1 was identified as a transcriptional repressor; however the protein remains associated with promoters of target genes after activation. Ng et al. show that Tup1 is SUMOylated under stress conditions, and that SUMOylation is required for persistence of Tup1 at active promoters.
- Chong Han Ng
- , Akhi Akhter
- & James L. Manley
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PRMT9 is a Type II methyltransferase that methylates the splicing factor SAP145
Protein arginine methylation is an abundant post-translational modification often associated with RNA-binding proteins. Here the authors show that the previously uncharacterized PRMT9 enzyme catalyses the symmetrical methylation of SAP145, which promotes its association with the SMN complex and regulates splicing.
- Yanzhong Yang
- , Andrea Hadjikyriacou
- & Mark T. Bedford
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| Open AccessArabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth
Suppression of MutS HOMOLOGUE 1 (MSH1), a plant protein targeted to mitochondria and plastids, causes a variety of phenotypes. Here Virdi et al. show that MSH1 depletion in Arabidopsisresults in heritable changes in nuclear DNA methylation, which can lead to enhanced growth vigour.
- Kamaldeep S. Virdi
- , John D. Laurie
- & Sally A. Mackenzie
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Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism
Histone lysine methylation plays crucial roles in controlling gene expression. Here the authors demonstrate that the activity of the histone lysine demethylase KDM5A is regulated through a feedback mechanism involving communication between the histone tail-binding and catalytic domains.
- Idelisse Ortiz Torres
- , Kristopher M. Kuchenbecker
- & Danica Galonić Fujimori
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| Open AccessMethylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan
Cellular pathways modulating longevity and stress resistance are known to affect protein translation. Here the authors show that the RNA methyltransferase, Nsun5, or its yeast homologue Rcm1, regulates lifespan of three different model organisms by modifying ribosomal RNA at a specific cytosine residue.
- Markus Schosserer
- , Nadege Minois
- & Johannes Grillari
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| Open AccessAugmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration through an unknown mechanism. Here, Yan et al.show that AMPK phosphorylates the novel substrate PDZ and LIM domain 5 (Pdlim5), and that phosphomimetic Pdlim5 impairs cell migration by disrupting the Rac1-Arp2/3 signalling pathway.
- Yi Yan
- , Osamu Tsukamoto
- & Seiji Takashima
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| Open AccessTemporal and spatial regulation of translation in the mammalian oocyte via the mTOR–eIF4F pathway
Meiotic maturation of oocytes and early development of mammalian embryos is largely dependent on the translation of mRNAs stored in the oocyte. Here the authors uncover a population of mRNA retained in the oocyte nucleus whose translation is spatially and temporally regulated by the mTOR–eIF4F pathway during meiosis.
- Andrej Susor
- , Denisa Jansova
- & Michal Kubelka
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Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination
Ubiquitination of cargo proteins regulates endocytosis in yeast and mammalian cells, however the extent to which this applies to plants is less clear. Martins et al. show that both internalization and vacuolar targetting of the Arabidopsisbrassinosteroid receptor BRI1 are regulated by ubiquitination.
- Sara Martins
- , Esther M. N. Dohmann
- & Grégory Vert
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FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51
The F-box DNA helicase 1 (FBH1) is implicated in suppression of homologous recombination (HR), but the precise mechanism is unclear. Here, the authors show that FBH1 can ubiquitylate RAD51, a central player in HR, and controls the subcellular localization of RAD51.
- Wai Kit Chu
- , Miranda J. Payne
- & Ian D. Hickson
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MARQUIS: A multiplex method for absolute quantification of peptides and posttranslational modifications
The absolute quantification of proteins and level of modifications between biological samples remain fraught with technical difficulties. Here, the authors present MARQUIS, a new mass spectrometry method that allows for precise absolute quantification of posttranslational modifications in complex protein samples.
- Timothy G. Curran
- , Yi Zhang
- & Forest M. White
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| Open AccessRb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells
In most human tumours, the cell cycle regulators Cdk4/6-cyclinD are overactive. Here the authors use C. elegansas a model system to identify downstream regulators that are critical in the response of tumour cells to Cdk4/6 inhibitors.
- Inge The
- , Suzan Ruijtenberg
- & Sander van den Heuvel
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Identification of a subnuclear body involved in sequence-specific cytokine RNA processing
Processing of interleukin RNAs must be tightly controlled during the immune response. Here, the authors identify TDP-43 as a scaffold protein for the formation of a nuclear body that is important for interleukin RNA processing and stability.
- Sungwook Lee
- , Taeyun A. Lee
- & Boyoun Park
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An acetylation switch controls TDP-43 function and aggregation propensity
The nuclear protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Here, Cohen et al. discover lysine acetylation as a modification that regulates TDP-43 function, providing a mechanism that could be implicated in the pathogenesis of TDP-43 proteinopathies.
- Todd J. Cohen
- , Andrew W. Hwang
- & Virginia M. Y. Lee
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| Open AccessThe Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation
Non-receptor tyrosine kinases such as Src play fundamental roles in host–pathogen interactions and phagocytosis. Here, Young et al. show that an enteropathogenic Escherichia coli(EPEC) protein, EspJ, inhibits Src activity by simultaneous amidation and ADP ribosylation of a conserved residue on the kinase.
- Joanna C. Young
- , Abigail Clements
- & Gad Frankel
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| Open AccessActivation of RidA chaperone function by N-chlorination
Hypochlorous acid generated by neutrophils acts as a potent antibacterial agent. Müller et al. now show that this oxidant directly activates a protective counter-response in E. coli by N-chlorinating the protein RidA and converting it into an effective protein chaperone.
- Alexandra Müller
- , Sina Langklotz
- & Lars Ingo Ole Leichert
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| Open AccessDynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans
The ubiquitin-like modifier SUMO is involved in many aspects of the cell cycle, but its dynamics during mitosis are unknown. Here, Pelisch et al.use C. elegans to show that SUMO accumulates on the metaphase plate and is required for proper chromosome alignment, and deconjugation is required to progress through the cell cycle.
- Federico Pelisch
- , Remi Sonneville
- & Ronald T. Hay
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Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage
SIRT1 is a deacetylase that is negatively regulated by binding to DBC1. Here Park et al.show that DNA damage-induced SUMO2/3 conjugation of DBC1 promotes the SIRT1–DBC1 interaction, leading to an increase in acetylated p53 and induction of apoptosis.
- Jong Ho Park
- , Seong Won Lee
- & Chin Ha Chung
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Kinetic modulation of a disordered protein domain by phosphorylation
Protein phosphorylation is a frequent biological occurrence, but the way in which this process modulates the disordered states of proteins is poorly understood. Here, the authors present simulations of the effect of phosphorylation on the kinetics and energetics of a disordered protein.
- Nathaniel Stanley
- , Santiago Esteban-Martín
- & Gianni De Fabritiis
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| Open AccessGlobal profiling of co- and post-translationally N-myristoylated proteomes in human cells
Protein N-myristoylation is a ubiquitous modification implicated in the regulation of multiple cellular processes. Here, Thinon et al. report the development of a general method to identify N-myristoylated proteins in human cells and identify over 100 endogenous post- and co-translational substrates of N-myristoyltransferase.
- Emmanuelle Thinon
- , Remigiusz A. Serwa
- & Edward W. Tate
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Site-specific mapping and quantification of protein S-sulphenylation in cells
Cysteine S-sulphenylation provides redox regulation of protein functions, but the extent of this post-translational modification in cells is unknown. Here, Yang et al. develop a method to detect hundreds of S-sulphenylation sites in cells, and show that many of them respond to a physiologically relevant redox stimulus.
- Jing Yang
- , Vinayak Gupta
- & Daniel C. Liebler
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ArhGAP30 promotes p53 acetylation and function in colorectal cancer
Tumour suppressor activity of p53 has been suggested to rely on acetylation of its C terminus. Here Wang and colleagues show that the Rho GTPase-activating protein ArhGAP30 is required for P300-mediated p53 acetylation and functional activation in colorectal cancer, and identify ArhGAP30 as a potential prognostic marker.
- Jilin Wang
- , Jin Qian
- & Jing-Yuan Fang
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Interplay between phosphorylation and SUMOylation events determines CESTA protein fate in brassinosteroid signalling
Brassinosteroid hormones control plant growth by regulating phosphorylation of a family of transcription factors. Here Khan et al.find that the stability and nuclear localization of the brassinosteroid-sensitive transcription factor CESTA is regulated by antagonistic SUMOylation and phosphorylation.
- Mamoona Khan
- , Wilfried Rozhon
- & Brigitte Poppenberger
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| Open AccessDiverse and divergent protein post-translational modifications in two growth stages of a natural microbial community
Characterizing post-translational modifications of proteins in microbial communities is challenging. Here, the authors identify and quantify a great number and diversity of such modifications in two growth stages of a natural microbial biofilm.
- Zhou Li
- , Yingfeng Wang
- & Chongle Pan
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Family-wide analysis of poly(ADP-ribose) polymerase activity
The poly(ADP-ribose) polymerase family of enzymes control many aspects of cellular signalling by covalently modifying proteins with either poly- or mono-(ADP-ribose). Vyas et al.catalogue the catalytic specificity of this family, and reveal that the majority of these enzymes generate only mono(ADP-ribose).
- Sejal Vyas
- , Ivan Matic
- & Paul Chang
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The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold
Two glycosyltransferase folds have been reported, GT-A and GT-B. Here, Zhang et al.report a 1.34 Å resolution structure of a domain of unknown function that adopts a new glycosylation fold, and show that the protein functions as a glycosyltransferase.
- Hua Zhang
- , Fan Zhu
- & Hui Wu
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Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding
While N-terminal acetylation has been shown to regulate the function or stability of a limited number of specific proteins, Holmes et al.report that global loss of this modification results in widespread protein misfolding, and show that the resulting stress response contributes to the suppression of a yeast prion phenotype.
- William M. Holmes
- , Brian K. Mannakee
- & Tricia R. Serio
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An RNA polymerase II-coupled function for histone H3K36 methylation in checkpoint activation and DSB repair
Chromatin modifications play a fundamental role in regulating the cellular response to DNA damage. Here, Jha and Strahl identify methylation of histone H3 on lysine 36 mediated by the histone-methyltransferase Set2 as a regulator of chromatin remodelling at double-strand breaks that affects DNA repair.
- Deepak Kumar Jha
- & Brian D. Strahl
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Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production
α-tubulin acetylation is an evolutionarily conserved modification but despite its prevalence, the physiological function of this process remains poorly understood. Here, the authors show that α-tubulin acetylation regulates p38 kinase signalling and expression of the anti-inflammatory cytokine IL-10 in macrophages.
- Bin Wang
- , Yan-Hua Rao
- & Tso-Pang Yao
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Article
| Open AccessReduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway
Haem oxygenase 1 produces carbon monoxide and this byproduct is known to alter cellular signalling. Here, the authors show that carbon monoxide alters the methylation of PFKFB3 in cancer cells resulting in deregulated cellular metabolism and the shunting of glucose into the pentose phosphate pathway.
- Takehiro Yamamoto
- , Naoharu Takano
- & Makoto Suematsu
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Dynamic phosphorylation of HP1α regulates mitotic progression in human cells
The chromatin-associated protein HP1α is known to also be involved in kinetochore assembly and sister chromatid cohesion. Chakraborty et al.show that phosphorylation at the hinge region of HP1α is required for the onset of mitosis, and facilitates Sgo1 binding to mitotic centromeres.
- Arindam Chakraborty
- , Kannanganattu V. Prasanth
- & Supriya G. Prasanth
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Article
| Open AccessThe nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A
The E3 ubiquitin ligase RNF168 ubiquitinates specific lysines on histone H2A as part of the DNA damage response. Here, the authors show that the acidic patch on the histone H2A/H2B dimer catalyses RNF168-dependent ubiquitination of histone 2A by redirecting ubiquitination activity towards the relevant target lysines.
- Francesca Mattiroli
- , Michael Uckelmann
- & Titia K. Sixma
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Sequence-based protein stabilization in the absence of glycosylation
Glycosylation is an essential process for preservation of protein structure and biological activity. Here, the authors show that the introduction of charge clusters containing specific amino-acid sequences can instead be used to control the stability and activity of non-glycosylated proteins.
- Nikki Y. Tan
- , Ulla-Maja Bailey
- & Benjamin L. Schulz
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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours
The majority of ovarian granulosa tumours harbour the C134W mutation in FOXL2 but the mechanism of tumorigenesis is largely unknown. Here, Kim et al. show that mutant FOXL2 is hyperphosphorylated by GSK3β, which targets the protein for degradation, and find that GSK3β inhibition represses the growth of ovarian granulosa cells.
- Jae-Hong Kim
- , Yong-Hak Kim
- & Jeehyeon Bae
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Article
| Open AccessSumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs
Cells secrete micro-RNAs by packaging them into exosomes; however, the mechanisms by which this packaging occurs are unclear. Here, the authors identify a sequence motif that confers exosomal targeting to micro-RNAs and identify a ribonucleoprotein complex that plays a role in this process.
- Carolina Villarroya-Beltri
- , Cristina Gutiérrez-Vázquez
- & Francisco Sánchez-Madrid
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Unexpected reactivity and mechanism of carboxamide activation in bacterial N-linked protein glycosylation
Oligosaccharyltransferases catalyse the transfer of lipid-anchored glycans onto acceptor asparagine residues in substrate proteins. By assaying chemically modified peptide substrate analogues, Lizak et al. rule out all but one of the currently postulated catalytic mechanisms for this enzyme.
- Christian Lizak
- , Sabina Gerber
- & Kaspar P. Locher
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Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60
Tip60 is a transcriptional coregulator that has an important role in differentiation. Here, Gao et al. demonstrate that the deubiquitination of Tip60 by USP7, a dominant deubiquitinating enzyme, is a key mechanism in early adipogenesis regulation.
- Yuan Gao
- , Arjen Koppen
- & Eric Kalkhoven
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An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms
Protein deacetylases of the sirtuin family have important roles in aging and metabolism. Using peptide microarrays displaying physiological lysine acetylation sites, the authors map the substrate preferences of all seven human sirtuin isoforms, revealing enzyme specificities and identifying new sirtuin substrates.
- David Rauh
- , Frank Fischer
- & Clemens Steegborn
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A systematic analysis of the PARP protein family identifies new functions critical for cell physiology
The poly(ADP-ribose) polymerase (PARP) family includes 17 proteins in humans, many of which have no known function. Vyas et al.systematically characterize the localization and function of each human PARP and identify PARP14 as a regulator of focal adhesions.
- Sejal Vyas
- , Melissa Chesarone-Cataldo
- & Paul Chang