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3 results on '"Barry Coull"'

1. FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.

Author

Elite Possik, Andrew Ajisebutu, Sanaz Manteghi, Marie-Claude Gingras, Tarika Vijayaraghavan, Mathieu Flamand, Barry Coull, Kathrin Schmeisser, Thomas Duchaine, Maurice van Steensel, David H Hall, and Arnim Pause

Subjects
Genetics, QH426-470
Abstract

Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5'-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis.

Published
2015
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2. Ubiquitin-Binding Domains in Y-Family Polymerases Regulate Translesion Synthesis

Author

Patricia Kannouche, Alan R. Lehmann, Ivan Dikic, Gerhard Wider, Grzegorz Zapart, Marzena Bienko, Nicola Crosetto, Kay Hofmann, Fabian Rudolf, Catherine M. Green, Matthias Peter, and Barry Coull

Subjects
DNA Replication, Models, Molecular, Xeroderma pigmentosum, DNA Repair, Ubiquitin binding, Protein Conformation, DNA repair, Recombinant Fusion Proteins, Amino Acid Motifs, Molecular Sequence Data, DNA-Directed DNA Polymerase, DNA polymerase eta, Transfection, Cell Line, Ubiquitin, Proliferating Cell Nuclear Antigen, Protein Interaction Mapping, medicine, Animals, Humans, Point Mutation, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, Xeroderma Pigmentosum, Multidisciplinary, biology, DNA replication, Computational Biology, Zinc Fingers, DNA, medicine.disease, Protein Structure, Tertiary, Proliferating cell nuclear antigen, Biochemistry, Mutation, DNA Polymerase iota, biology.protein, REV1, Hydrophobic and Hydrophilic Interactions, DNA Damage, Protein Binding
Abstract

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)–binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of polη and polι to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of polη is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

Published
2005
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3. Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells

Author

Alan R. Lehmann, Barry Coull, Antonio E. Vidal, Roger Woodgate, Colin Gray, Antonio R. Fernández de Henestrosa, Daniel Zicha, and Patricia Kannouche

Subjects
DNA Replication, DNA polymerase, DNA damage, Ultraviolet Rays, Recombinant Fusion Proteins, Active Transport, Cell Nucleus, DNA polymerase eta, DNA-Directed DNA Polymerase, Spodoptera, Transfection, General Biochemistry, Genetics and Molecular Biology, Cell Line, chemistry.chemical_compound, Genes, Reporter, Caffeine, Two-Hybrid System Techniques, Protein Interaction Mapping, Animals, Humans, Molecular Biology, Polymerase, Cell Line, Transformed, Sequence Deletion, Genetics, Cell Nucleus, Xeroderma Pigmentosum, Models, Genetic, General Immunology and Microbiology, biology, DNA synthesis, General Neuroscience, Genetic Complementation Test, DNA replication, DNA, Articles, Fibroblasts, Immunohistochemistry, Cell biology, chemistry, Microscopy, Fluorescence, DNA Polymerase iota, biology.protein, DNA Polymerase Iota, Protein Binding, DNA Damage
Abstract

Y-family DNA polymerases can replicate past a variety of damaged bases in vitro but, with the exception of DNA polymerase eta (poleta), which is defective in xeroderma pigmentosum variants, there is little information on the functions of these polymerases in vivo. Here, we show that DNA polymerase iota (poliota), like poleta, associates with the replication machinery and accumulates at stalled replication forks following DNA-damaging treatment. We show that poleta and poliota foci form with identical kinetics and spatial distributions, suggesting that localization of these two polymerases is tightly co-ordinated within the nucleus. Furthermore, localization of poliota in replication foci is largely dependent on the presence of poleta. Using several different approaches, we demonstrate that poleta and poliota interact with each other physically and that the C-terminal 224 amino acids of poliota are sufficient for both the interaction with poleta and accumulation in replication foci. Our results provide strong evidence that poleta targets poliota to the replication machinery, where it may play a general role in maintaining genome integrity as well as participating in translesion DNA synthesis.

Published
2002

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