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      HMGB1 interacts with human topoisomerase IIα and stimulates its catalytic activity

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          Abstract

          DNA topoisomerase IIα (topo IIα) is an essential nuclear enzyme and its unique decatenation activity has been implicated in many aspects of chromosome dynamics such as chromosome replication and segregation during mitosis. Here we show that chromatin-associated protein HMGB1 (a member of the large family of HMG-box proteins with possible functions in DNA replication, transcription, recombination and DNA repair) promotes topo IIα-mediated catenation of circular DNA, relaxation of negatively supercoiled DNA and decatenation of kinetoplast DNA. HMGB1 interacts with topo IIα and this interaction, like the stimulation of the catalytic activity of the enzyme, requires both HMG-box domains of HMGB1. A mutant of HMGB1, which cannot change DNA topology stimulates DNA decatenation by topo IIα indistinguishably from the wild-type protein. Although HMGB1 stimulates ATP hydrolysis by topo IIα, the DNA cleavage is much more enhanced. The observed abilities of HMGB1 to interact with topo IIα and promote topo IIα binding to DNA suggest a mechanism by which HMGB1 stimulates the catalytic activity of the enzyme via enhancement of DNA cleavage.

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          Most cited references 54

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          Cellular roles of DNA topoisomerases: a molecular perspective.

          DNA topoisomerases are the magicians of the DNA world by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.
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            Macromolecular crowding: obvious but underappreciated.

             R.John Ellis (2001)
            Biological macromolecules evolve and function within intracellular environments that are crowded with other macromolecules. Crowding results in surprisingly large quantitative effects on both the rates and the equilibria of interactions involving macromolecules, but such interactions are commonly studied outside the cell in uncrowded buffers. The addition of high concentrations of natural and synthetic macromolecules to such buffers enables crowding to be mimicked in vitro, and should be encouraged as a routine variable to study. The stimulation of protein aggregation by crowding might account for the existence of molecular chaperones that combat this effect. Positive results of crowding include enhancing the collapse of polypeptide chains into functional proteins, the assembly of oligomeric structures and the efficiency of action of some molecular chaperones and metabolic pathways.
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              The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice.

              High mobility group 1 (HMG1) protein is an abundant component of all mammalian nuclei, and related proteins exist in all eukaryotes. HMG1 binds linear DNA with moderate affinity and no sequence specificity, but bends the double helix significantly on binding through the minor groove. It binds with high affinity to DNA that is already sharply bent, such as linker DNA at the entry and exit of nucleosomes; thus, it is considered a structural protein of chromatin. HMG1 is also recruited to DNA by interactions with proteins required for basal and regulated transcriptions and V(D)J recombination. Here we generate mice harbouring deleted Hmg1. Hmg1-/- pups are born alive, but die within 24 hours due to hypoglycaemia. Hmg1-deficient mice survive for several days if given glucose parenterally, then waste away with pleiotropic defects (but no alteration in the immune repertoire). Cell lines lacking Hmg1 grow normally, but the activation of gene expression by the glucocorticoid receptor (GR, encoded by the gene Grl1) is impaired. Thus, Hmg1 is not essential for the overall organization of chromatin in the cell nucleus, but is critical for proper transcriptional control by specific transcription factors.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                August 2007
                18 July 2007
                18 July 2007
                : 35
                : 15
                : 5001-5013
                Affiliations
                1Laboratory of Analysis of Chromosomal Proteins, Academy of Sciences of the Czech Republic, Institute of Biophysics, Brno, 2Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic and 3Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France
                Author notes
                *To whom correspondence should be addressed.+420 541517183+420 541211293 stros@ 123456ibp.cz Correspondence may also be addressed to François Strauss.+33 142346941+33 142346893 fstrauss@ 123456ccr.jussieu.fr
                Article
                10.1093/nar/gkm525
                1976466
                17636313
                © 2007 The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Nucleic Acid Enzymes

                Genetics

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