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Am J Hum Genet 2021 Apr 19;108(4):749-756. Epub 2021 Mar 19.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Newborn Screening Ontario, Ottawa, ON K1H 8L1, Canada.

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. Read More

Viruses 2021 02 12;13(2). Epub 2021 Feb 12.

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs). The matrix proteins utilize proline-rich Late (L) domain motifs (e. Read More

Biochem Pharmacol 2020 12 1;182:114255. Epub 2020 Oct 1.

Dept. of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Oxaliplatin-induced neuropathy (OXAIN) is a major adverse effect of this antineoplastic drug, widely used in the treatment of colorectal cancer. Although its molecular mechanisms remain poorly understood, recent evidence suggest that maladaptive neuroplasticity and oxidative stress may participate to the development of this neuropathy. Given the role played on protein remodeling by ubiquitin-proteasome system (UPS) in response to oxidative stress and in neuropathic pain, we investigated whether oxaliplatin might cause alterations in the UPS-mediated degradation pathway, in order to identify new pharmacological tools useful in OXAIN. Read More

Biophys J 2020 10 11;119(8):1558-1567. Epub 2020 Sep 11.

Institut für Physikalische Chemie, Westfälische Wilhelms-Universität Münster, Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms-Universität Münster, Münster, Germany. Electronic address:

Post-translational modification with one of the isoforms of the small ubiquitin-like modifier (SUMO) affects thousands of proteins in the human proteome. The binding of SUMO to SUMO interacting motifs (SIMs) can translate the SUMOylation event into functional consequences. The E3 ubiquitin ligase RNF4 contains multiple SIMs and connects SUMOylation to the ubiquitin pathway. Read More

Drug Metab Dispos 2020 07 29;48(7):544-552. Epub 2020 Apr 29.

Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia

Several cytochrome P450 enzymes are known to be down-regulated by nitric oxide (NO). CYP2A6 is responsible for the metabolism of nicotine and several other xenobiotics, but its susceptibility to down-regulation by NO has not been reported. To address this question, we used Huh7 human hepatoma cell lines to express CYP2A6 with a C-terminal V5 tag (CYP2A6V5). Read More

Proc Natl Acad Sci U S A 2020 04 19;117(14):7950-7960. Epub 2020 Mar 19.

Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093

Intracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematode called the intracellular pathogen response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. Read More

PLoS One 2020 16;15(1):e0227841. Epub 2020 Jan 16.

Department of Biochemistry, Stanford University, Stanford, CA, United States of America.

The Ribosome-associated Quality Control (RQC) pathway co-translationally marks incomplete polypeptides from stalled translation with two signals that trigger their proteasome-mediated degradation. The E3 ligase Ltn1 adds ubiquitin and Rqc2 directs the large ribosomal subunit to append carboxy-terminal alanine and threonine residues (CAT tails). When excessive amounts of incomplete polypeptides evade Ltn1, CAT-tailed proteins accumulate and can self-associate into aggregates. Read More

Plant Mol Biol 2020 Mar 8;102(4-5):537-551. Epub 2020 Jan 8.

Bioengineering College, Chongqing University, Chongqing, 400044, China.

Key Message: Silencing of SlCAND1 expression resulted in dwarfish, loss of apical dominance, early flowering, suppression of seed germination, and abnormal root architecture in tomato Cullin-RING E3 ligases (CRLs)-dependent ubiquitin proteasome system mediates degradation of numerous proteins that controls a wide range of developmental and physiological processes in eukaryotes. Cullin-associated Nedd8-dissociated protein 1 (CAND1) acts as an exchange factor allowing substrate recognition part exchange and plays a vital role in reactivating CRLs. The present study reports on the identification of SlCAND1, the only one CAND gene in tomato. Read More

J Virol 2020 02 14;94(5). Epub 2020 Feb 14.

Daniella Lee Casper Laboratory in Viral Oncology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. In a previous study, we have identified LANA-interacting proteins using a protein array screen. Here, we explore the effect of LANA on the stability and activity of RLIM (RING finger LIM-domain-interacting protein, encoded by the gene), a novel LANA-interacting protein identified in that protein screen. Read More

Mol Genet Genomic Med 2019 08 29;7(8):e786. Epub 2019 Jun 29.

INSERM U1253 ibrain, Université de Tours, Tours, France.

Background: There is a strong evidence for genetic factors as the main causes of Autism Spectrum Disorders (ASD). To date, hundreds of genes have been identified either by copy number variations (CNVs) and/or single nucleotide variations. However, despite all the findings, the genetics of these disorders have not been totally explored. Read More

Mol Cell Proteomics 2019 07 10;18(7):1428-1436. Epub 2019 May 10.

From the ‡School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, IRELAND;; §Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland;. Electronic address:

SETD1A is a SET domain-containing methyltransferase involved in epigenetic regulation of transcription. It is the main catalytic component of a multiprotein complex that methylates lysine 4 of histone H3, a histone mark associated with gene activation. In humans, six related protein complexes with partly nonredundant cellular functions share several protein subunits but are distinguished by unique catalytic SET-domain proteins. Read More

Mol Cancer 2019 04 3;18(1):77. Epub 2019 Apr 3.

Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.

Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Read More

Biol Cell 2019 Mar 8;111(3):67-77. Epub 2019 Feb 8.

Cellular Microbiology and Physics of Infection Group, Center for Infection and Immunity of Lille, CNRS UMR8204, INSERM U1019, Institut Pasteur de Lille, Lille regional Univ. Hosp. Centr., Lille Univ., Lille, F-59019, France.

Background: Bacterial invasion covers two steps: adhesion and entry per se. The cell signalling response is triggered upon pathogen interaction at the cell surface. This response continues when the pathogen is internalised. Read More

Sci Rep 2019 01 18;9(1):208. Epub 2019 Jan 18.

Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA.

Epstein-Barr Virus latent membrane protein-1 (LMP1) interacts with the SUMO-conjugating enzyme Ubc9, which induces protein sumoylation and may contribute to LMP1-mediated oncogenesis. After analyzing human lymphoma tissues and EBV-positive cell lines, we now document a strong correlation between LMP1 and sumo-1/2/3 or SUMO-1/2/3 levels, and show that LMP1-induced sumo expression requires the activation of NF-κB signaling through CTAR1 and CTAR2. Together, these results point to a second mechanism by which LMP1 dysregulates sumoylation processes and adds EBV-associated lymphomas to the list of malignancies associated with increased SUMO expression. Read More

Nat Commun 2019 01 11;10(1):166. Epub 2019 Jan 11.

Neuro-Network Evolution Project, Advanced ICT Research Institute, National Institute of Information and Communications Technology (NICT), 588-2 Iwaoka, Nishi-ku, Kobe, 651-2492, Japan.

In Drosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate inducer on the pleiotropic transcription factor Longitudinals lacking (Lola). Surprisingly, Fruitless, another transcription factor with a master regulator role for courtship circuitry formation, directly binds to Lola to protect its cleavage in males. Read More

Biochem Biophys Res Commun 2019 02 22;509(2):348-353. Epub 2018 Dec 22.

Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, 421 E Canfield Street, Detroit, MI, 48201, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA. Electronic address:

The E3 ubiquitin (Ub) ligase gp78 plays an important role in endoplasmic reticulum (ER)-associated degradation (ERAD) and regulation of lipid biogenesis. Although a variety of substrates of gp78 have been described, the regulation of the degradation of gp78 itself remains poorly understood. To address this problem, we used co-immunoprecipitation-coupled liquid chromatography-tandem mass spectrometry (Co-IP/LC-MS/MS) to identify novel proteins interacting with gp78. Read More

BMC Genomics 2018 Dec 13;19(1):926. Epub 2018 Dec 13.

ISGlobal, 08003, Barcelona, Spain.

Background: Genes corregulate their overall transcript volumes to perform their physiological functions. However, it is unknown if they additionally coregulate their transcript diversities. We studied the reliability, consistency and functional associations of co-splicing correlations of genes of interest, across two independent studies, multiple tissues and two statistical methods. Read More

Redox Biol 2019 01 17;20:533-543. Epub 2018 Nov 17.

Department of Human Biology, The Faculty of Natural Sciences, University of Haifa, Haifa 3190500, Israel; Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel. Electronic address:

Cycles of Cdc53/Cullin1 rubylation (a.k.a NEDDylation) protect ubiquitin-E3 SCF (Skp1-Cullin1-F-box protein) complexes from self-destruction and play an important role in mediating the ubiquitination of key protein substrates involved in cell cycle progression, development, and survival. Read More

Protein J 2018 12;37(6):500-509

Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4000, South Africa.

Covalent inhibition has recently gained a resurgence of interest in several drug discovery areas. The expansion of this approach is based on evidence elucidating the selectivity and potency of covalent inhibitors when bound to particular amino acids of a biological target. The Nedd4-1, an E3 ubiquitin ligase, is characterized by two covalent binding sites, of which catalytic Cys and allosteric Cys are enclosed. Read More

Ann Neurol 2018 10 15;84(4):485-496. Epub 2018 Sep 15.

Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, United Kingdom.

Objective: The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome-wide association study (GWAS) to identify genetic determinants of PSP phenotype.

Methods: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non-RS groups. Read More

Nucleic Acids Res 2018 04;46(6):3218-3231

School of Biomedical Sciences, The University of Hong Kong, PokFuLam, Hong Kong.

UHRF1 plays multiple roles in regulating DNMT1-mediated DNA methylation maintenance during DNA replication. The UHRF1 C-terminal RING finger functions as an ubiquitin E3 ligase to establish histone H3 ubiquitination at Lys18 and/or Lys23, which is subsequently recognized by DNMT1 to promote its localization onto replication foci. Here, we present the crystal structure of DNMT1 RFTS domain in complex with ubiquitin and highlight a unique ubiquitin binding mode for the RFTS domain. Read More

Biochem Biophys Res Commun 2018 02 8;497(1):127-132. Epub 2018 Feb 8.

Department of Molecular & Cellular Biochemistry, Centre for Structural Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA. Electronic address:

Sucrose non-fermenting 1-related protein kinase 1 (SnRK1) is a central metabolic regulator and the plant orthologue of the mammalian AMP-activated protein kinase (AMPK); both are energy-sensing heterotrimeric enzymes comprising a catalytic α- and regulatory β- and γ-subunits. α-Subunits contain a serine/threonine kinase domain (KD) at their N-terminus that is immediately followed by a small regulatory domain termed the auto-inhibitory domain (AID) in AMPK and the ubiquitin-associated domain (UBA) in SnRK1. Association of the AID with the AMPK KD inhibits activating phosphorylation of the KD by upstream kinases and promotes dephosphorylation, as well as inhibiting AMPK catalytic activity. Read More

Nat Commun 2018 02 9;9(1):613. Epub 2018 Feb 9.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-αβ (IFNαβ) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNαβ production to induce anti-DNA viral immunity. Read More

Proc Natl Acad Sci U S A 2018 02 31;115(7):1558-1563. Epub 2018 Jan 31.

Department of Medicine, University of Washington, Seattle, WA 98195;

RING1 is an E3-ubiquitin ligase that is involved in epigenetic control of transcription during development. It is a component of the polycomb repressive complex 1, and its role in that complex is to ubiquitylate histone H2A. In a 13-year-old girl with syndromic neurodevelopmental disabilities, we identified a de novo mutation, RING1 p. Read More

Structure 2018 02 18;26(2):249-258.e4. Epub 2018 Jan 18.

Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Max-von-Laue Strasse 9, 60438 Frankfurt am Main, Germany. Electronic address:

Ubiquitination is the most versatile posttranslational modification. The information is encoded by linkage type as well as chain length, which are translated by ubiquitin binding domains into specific signaling events. Chain topology determines the conformational space of a ubiquitin chain and adds an additional regulatory layer to this ubiquitin code. Read More

Cell 2018 01 28;172(3):439-453.e14. Epub 2017 Dec 28.

The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1 cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. Read More

EMBO Rep 2017 11 8;18(11):1922-1934. Epub 2017 Sep 8.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China

The Hh pathway controls many morphogenetic processes in metazoans and plays important roles in numerous pathologies and in cancer. Hh signaling is mediated by the activity of the Gli/Ci family of transcription factors. Several studies in have shown that ubiquitination by the ubiquitin E3 ligases Slimb and Rdx(Hib) plays a crucial role in controlling Ci stability dependent on the levels of Hh signals. Read More

J Clin Neuromuscul Dis 2017 Sep;19(1):5-11

*Department of Internal Medicine, Division of Neurology, King Abdulaziz University, Jeddah, Saudi Arabia; Departments of †Physical Therapy and ‡Anatomy and Cell Biology, The University of Kansas Medical Center, Kansas City, KS; §Clinical and Translational Science Unit, The University of Kansas Medical Center, Kansas City, KS; and ¶Department of Neurology, The University of Kansas Medical Center, Kansas City, KS.

Objectives: To compare the frequency of abnormalities in epidermal nerve fiber density (ENFD) and quantitative sudomotor axon reflex (QSART) in patients with diabetic distal symmetric polyneuropathy (DSPN).

Methods: Nerve conduction studies, ENFD, and QSART data were obtained pre- and postexercise, in patients enrolled in a prospective diabetic neuropathy study. McNemar's test was applied to compare the yield of ENFD and QSART. Read More

Cell Cycle 2017 Oct 18;16(19):1744-1747. Epub 2017 Aug 18.

a Department of Pediatric Hematology and Oncology , IRCSS Bambino Gesù Children's Hospital , Rome , Italy.

Autophagy is a highly conserved process that acts sequestering cytoplasmic components for their degradation by the lysosomes. It consists of several sequential steps that have to be finely regulated to ensure both its progression and termination. Post-translational modifications (PTMs) play an important role in regulating ATG proteins function in different stages of autophagy. Read More

Mod Pathol 2017 11 28;30(11):1577-1588. Epub 2017 Jul 28.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. Read More