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Robert C A M van Waardenburg
Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H(493)R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex...
2016: Journal of Neurology & Neuromedicine
Guoqiang Ma, Shuang Li, Yuhong Han, Shuangxi Li, Tao Yue, Bing Wang, Jin Jiang
Hedgehog (Hh) signaling plays a central role in development and diseases. Hh activates its signal transducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifications remains unexplored. Here we show that sumoylation acts in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling. We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1. Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-surface accumulation and elevated Hh pathway activity...
October 7, 2016: Developmental Cell
Baijun Dong, Yujing Gao, Xunlei Kang, Hongchang Gao, Jin Zhang, Hua Guo, Mingjian J You, Wei Xue, Jinke Cheng, Yiran Huang
Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC...
October 12, 2016: Oncotarget
Serena Marcelli, Elena Ficulle, Filomena Iannuzzi, Enikö Kövari, Robert Nisticò, Marco Feligioni
Synaptic dysfunction has been recognized as an early feature occurring at the onset of Alzheimer's disease (AD). Compromised neurotransmission leads over time to synaptic loss and these events correlate with the cognitive decline that progressively affects AD patients.Protein SUMOylation (Small Ubiquitin-like MOdifier) is a post-translational modification (PTM) involved in several cellular processes including synaptic transmission.We here demonstrate that cortical synaptosomes prepared from Tg2576 mice of 6 months of age show an increased SUMO-1ylation, which returns back to normal levels at 20 months although synaptic SUMOylation, at this age, resulted more sensible to KCl stimulus...
October 13, 2016: Molecular Neurobiology
Kazushiro Fujiwara, Koichi Hasegawa, Masahiro Oka, Yoshihiro Yoneda, Kazuaki Yoshikawa
Terminal differentiation of neurons is accompanied by irreversible exit from the cell cycle and expression of neuronal phenotypes. The molecular mechanism whereby committed neuronal progenitors lose their ability to reenter the cell cycle is largely unknown. Here, we report that the nuclear transport system is rapidly remodeled in primary cortical progenitor cells (CPCs) at the very beginning of neuronal terminal differentiation. High levels of Ran GTPase-activating protein 1 (RanGAP), a key regulator of the Ran GTP-GDP cycle, in primary CPCs are drastically reduced upon neuronal induction...
September 22, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Aminat T Oki, Bernice Huang, Andrea R Beyer, Levi J May, Hilary K Truchan, Naomi J Walker, Nathan L Galloway, Dori L Borjesson, Jason A Carlyon
Anaplasma phagocytophilum, a member of the family Anaplasmataceae and the obligate intracellular bacterium that causes granulocytic anaplasmosis, resides in a host cell-derived vacuole. Bacterial proteins that localize to the A. phagocytophilum-occupied vacuole membrane (AVM) are critical host-pathogen interfaces. Of the few bacterial AVM proteins that have been identified, the domains responsible for AVM localization and the host cell pathways that they co-opt are poorly defined. APH0032 is an effector that is expressed and localizes to the AVM late during the infection cycle...
2016: Frontiers in Cellular and Infection Microbiology
Sisi Liu, Jianyin Long, Bo Yuan, Mingjie Zheng, Mu Xiao, Jianming Xu, Xia Lin, Xin-Hua Feng
Smad nuclear interacting protein-1 (SNIP1) is a transcription repressor for the TGF-β and NF-κB signaling pathways through disrupting the recruitment of coactivator p300. However, it is unclear how the functions of SNIP1 in the TGF-β signaling pathway are controlled. Our present studies show that SNIP1 is covalently modified by SUMO in vitro and in vivo at three lysine sites: Lys5, Lys30 and Lys108, with Lys30 being the major SUMO modification site. SUMOylation of SNIP1 is enhanced by SUMO E3 ligases PIAS proteins and inhibited by SUMO proteases SENP1/2...
October 4, 2016: Journal of Biological Chemistry
Jai Shankar Singh, Vaibhav Kumar Shukla, Mansi Gujrati, Ram Kumar Mishra, Ashutosh Kumar
One of the most debilitating diseases Malaria, in its different forms, is caused by protozoan of Plasmodium species. Deadliest among these forms is the "cerebral malaria" which is afflicted upon by Plasmodium falciparum. Plasmodium adopts numerous strategies including various post-translational modifications (PTMs) to infect and survive in the human host. These PTMs have proven their critical requirement in the Plasmodium biology. Recently, sumoylation has been characterized as one of the important PTMs and many of its putative substrates have been identified in Plasmodium...
October 3, 2016: Biomolecular NMR Assignments
Johnathan Neiswinger, Ijeoma Uzoma, Eric Cox, HeeSool Rho, Jun Seop Jeong, Heng Zhu
Protein microarray technology provides a straightforward yet powerful strategy for identifying substrates of posttranslational modifications (PTMs) and studying the specificity of the enzymes that catalyze these reactions. Protein microarray assays can be designed for individual enzymes or a mixture to establish connections between enzymes and substrates. Assays for four well-known PTMs-phosphorylation, acetylation, ubiquitylation, and SUMOylation-have been developed and are described here for use on functional protein microarrays...
October 3, 2016: Cold Spring Harbor Protocols
Marek Sebesta, Madhusoodanan Urulangodi, Barbora Stefanovie, Barnabas Szakal, Martin Pacesa, Michael Lisby, Dana Branzei, Lumir Krejci
Replication across damaged DNA templates is accompanied by transient formation of sister chromatid junctions (SCJs). Cells lacking Esc2, an adaptor protein containing no known enzymatic domains, are defective in the metabolism of these SCJs. However, how Esc2 is involved in the metabolism of SCJs remains elusive. Here we show interaction between Esc2 and a structure-specific endonuclease Mus81-Mms4 (the Mus81 complex), their involvement in the metabolism of SCJs, and the effects Esc2 has on the enzymatic activity of the Mus81 complex...
September 30, 2016: Nucleic Acids Research
Wenrong Xia, Hongwei Tian, Xin Cai, HaiBo Kong, Wenliang Fu, Weiwei Xing, Yuanyuan Wang, Minji Zou, Yuhua Hu, Donggang Xu
SUMO-specific protease 1 (SENP1) is an important regulation protease in the protein desumoylation, which was shown to have a prooncogenicrole in many types of cancer. However, the mechanism of action for SENP1 in astrocytoma is not yet clear. Astrocytoma is the most frequent one among various neurogliomas, of which a subtype known as glioblastoma multiforme (GBM) is the most malignant brain glioma and seriously influences the life quality of the patients. In this study, the expression of SENP1 was detected in 28 cases of various grades of astrocytoma and 6 cases of normal human tissues...
September 28, 2016: Gene
Santosh Kumar Yadav, Indrasen Magre, Aditi Singh, Deepak Khuperkar, Jomon Joseph
Atypical PKC (aPKC) family members are involved in regulation of diverse cellular processes, including cell polarization. aPKCs are known to be activated by phosphorylation of specific threonine residues in the activation loop and turn motif. They can also be stimulated by interaction with Cdc42~GTP-Par6 complex. Here we report that PKCζ, a member of the aPKC family, is activated by SUMOylation. We show that aPKC is endogenously modified by SUMO1 and the nucleoporin Nup358 acts as its SUMO E3 ligase. Results from in vitro SUMOylation and kinase assays showed that the modification enhances the kinase activity of PKCζ by ~10-fold...
September 29, 2016: Scientific Reports
Caroline E Weller, Abhinav Dhall, Feizhi Ding, Edlaine Linares, Samuel D Whedon, Nicholas A Senger, Elizabeth L Tyson, John D Bagert, Xiaosong Li, Ohara Augusto, Champak Chatterjee
Access to protein substrates homogenously modified by ubiquitin (Ub) is critical for biophysical and biochemical investigations aimed at deconvoluting the myriad biological roles for Ub. Current chemical strategies for protein ubiquitylation, however, employ temporary ligation auxiliaries that are removed under harsh denaturing conditions and have limited applicability. We report an unprecedented aromatic thiol-mediated N-O bond cleavage and its application towards native chemical ubiquitylation with the ligation auxiliary 2-aminooxyethanethiol...
2016: Nature Communications
Anthony DiBello, Ajit B Datta, Xiangbin Zhang, Cynthia Wolberger
Members of the RING E3 ubiquitin ligase family bind to both substrate and ubiquitin-charged E2 enzyme, promoting transfer of ubiquitin from the E2 to substrate. Either a single ubiquitin or one of several types of polyubiquitin chains can be conjugated to substrate proteins, with different types of ubiquitin modifications signaling distinct outcomes. E2 enzymes play a central role in governing the nature of the ubiquitin modification, although the essential features of the E2 that differentiate mono- versus polyubiquitinating E2 enzymes remain unclear...
September 24, 2016: Journal of Molecular Biology
Taehyun Ryu, Melissa Bonner, Irene Chiolo
Repairing double-strand breaks (DSBs) is particularly challenging in heterochromatin, where the abundance of repeated sequences exacerbates the risk of ectopic recombination and chromosome rearrangements. In Drosophila cells, faithful homologous recombination (HR) repair of heterochromatic DSBs relies on a specialized pathway that relocalizes repair sites to the nuclear periphery before Rad51 recruitment. Here we show that HR progression is initially blocked inside the heterochromatin domain by SUMOylation and the coordinated activity of two distinct Nse2 SUMO E3 ligases: Quijote (Qjt) and Cervantes (Cerv)...
September 27, 2016: Nucleus
Bertrand Colignon, Edouard Delaive, Marc Dieu, Catherine Demazy, Yordan Muhovski, Cindy Wallon, Martine Raes, Sergio Mauro
: SUMOylation is a post-translational modification which regulates a number of critical biological processes in, for example mammals, yeast and plants. In order to fully understand the functional effects of SUMOylation an essential first step is the identification of endogenous targets for SUMOylation. Here we report the results of using a recently developed proteomic approach based on the use of 3D gels to identify the endogenous SUMO targets in leaves of Solanum tuberosum. By using 3D gels we avoid the problem of co-migration of proteins, which is a major limitation of 2D gels, and we enable the use of the highly sensitive CyDye DIGE fluor saturation dyes...
September 23, 2016: Journal of Proteomics
Emilio Lecona, Oscar Fernandez-Capetillo
Post-translational modifications regulate each step of DNA replication to ensure the faithful transmission of genetic information. In this context, we recently showed that deubiquitination of SUMO2/3 and SUMOylated proteins by USP7 helps to create a SUMO-rich and ubiquitin-low environment around replisomes that is necessary to maintain the activity of replication forks and for new origin firing. We propose that a two-flag system mediates the collective concentration of factors at sites of DNA replication, whereby SUMO and Ubiquitinated-SUMO would constitute "stay" or "go" signals respectively for replisome and accessory factors...
September 26, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Elisa Da Silva-Ferrada, Teresa M Ribeiro-Rodrigues, Manuel S Rodríguez, Henrique Girão
Heart proteostasis relies on a complex and integrated network of molecular processes surveilling organ performance under physiological and pathological conditions. For this purpose, cardiac cells depend on the correct function of their proteolytic systems, such as the ubiquitin-proteasome system (UPS), autophagy and the calpain system. Recently, the role of protein SUMOylation (an ubiquitin-like modification), has emerged as important modulator of cardiac proteostasis, which will be the focus of this review...
October 2016: International Journal of Biochemistry & Cell Biology
Ching-Yi Tsai, Faith C H Li, Carol H Y Wu, Alice Y W Chang, Samuel H H Chan
BACKGROUND: Small ubiquitin-related modifier (SUMO) is a group of proteins that participates in post-translational modifications. One known SUMO target is the transcription factor nuclear factor-kB (NF-kB) that plays a pivotal role in many disease processes; sumoylation inactivates NF-kB by conjugation with inhibitors of NF-kB (IkB). Our laboratory demonstrated previously that transcriptional upregulation of nitric oxide synthase II (NOS II) by NF-kB, leading to nitrosative stress by the formation of peroxynitrite in the rostral ventrolateral medulla (RVLM), underpins the defunct brain stem cardiovascular regulation that precedes brain death...
2016: Journal of Biomedical Science
Sook-Young Sohn, Patrick Hearing
The human adenovirus genome is transported into the nucleus, where viral gene transcription, viral DNA replication, and virion assembly take place. Posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are implicated in the regulation of diverse cellular processes, particularly nuclear events. It is not surprising, therefore, that adenovirus modulates and utilizes the host sumoylation system. Adenovirus early proteins play an important role in establishing optimal host environments for virus replication within infected cells by stimulating the cell cycle and counteracting host antiviral defenses...
2016: MBio
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