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      The ring-shaped hexameric helicases that function at DNA replication forks

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      Nature Structural & Molecular Biology
      Springer Nature

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          Abstract

          <p class="first" id="P1">DNA replication requires separation of genomic duplex DNA strands that is performed by hexameric ring shaped helicase machines in all domains of life. The structures and chemo-mechanical actions of these fascinating machines are coming into focus. There is no evolutionary relationship between the hexameric helicases of bacteria and archaea/eukaryotes, yet they share many fundamental features. We review recent studies on these two groups of hexameric helicases that have unveiled some very surprising distinctions. </p>

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          Structure and mechanism of helicases and nucleic acid translocases.

          Helicases and translocases are a ubiquitous, highly diverse group of proteins that perform an extraordinary variety of functions in cells. Consequently, this review sets out to define a nomenclature for these enzymes based on current knowledge of sequence, structure, and mechanism. Using previous definitions of helicase families as a basis, we delineate six superfamilies of enzymes, with examples of crystal structures where available, and discuss these structures in the context of biochemical data to outline our present understanding of helicase and translocase activity. As a result, each superfamily is subdivided, where appropriate, on the basis of mechanistic understanding, which we hope will provide a framework for classification of new superfamily members as they are discovered and characterized.
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            Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.

            The licensing of eukaryotic DNA replication origins, which ensures once-per-cell-cycle replication, involves the loading of six related minichromosome maintenance proteins (Mcm2-7) into prereplicative complexes (pre-RCs). Mcm2-7 forms the core of the replicative DNA helicase, which is inactive in the pre-RC. The loading of Mcm2-7 onto DNA requires the origin recognition complex (ORC), Cdc6, and Cdt1, and depends on ATP. We have reconstituted Mcm2-7 loading with purified budding yeast proteins. Using biochemical approaches and electron microscopy, we show that single heptamers of Cdt1*Mcm2-7 are loaded cooperatively and result in association of stable, head-to-head Mcm2-7 double hexamers connected via their N-terminal rings. DNA runs through a central channel in the double hexamer, and, once loaded, Mcm2-7 can slide passively along double-stranded DNA. Our work has significant implications for understanding how eukaryotic DNA replication origins are chosen and licensed, how replisomes assemble during initiation, and how unwinding occurs during DNA replication.
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              Regulated Eukaryotic DNA Replication Origin Firing with Purified Proteins

              Eukaryotic cells initiate DNA replication from multiple origins, which must be tightly regulated to promote precise genome duplication in every cell cycle. To accomplish this, initiation is partitioned into two temporally discrete steps: a double hexameric MCM complex is first loaded at replication origins during G1 phase, and then converted to the active CMG (Cdc45, MCM, GINS) helicase during S phase. Here we describe the reconstitution of budding yeast DNA replication initiation with 16 purified replication factors, made from 42 polypeptides. Origin-dependent initiation recapitulates regulation seen in vivo. Cyclin dependent kinase (CDK) inhibits MCM loading by phosphorylating the origin recognition complex (ORC) and promotes CMG formation by phosphorylating Sld2 and Sld3. Dbf4 dependent kinase (DDK) promotes replication by phosphorylating MCM, and can act either before or after CDK. These experiments define the minimum complement of proteins, protein kinase substrates and co-factors required for regulated eukaryotic DNA replication.
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                Author and article information

                Journal
                Nature Structural & Molecular Biology
                Nat Struct Mol Biol
                Springer Nature
                1545-9993
                1545-9985
                January 29 2018
                :
                :
                Article
                10.1038/s41594-018-0024-x
                5876725
                29379175
                75bf4e63-1f32-4805-bf6f-662fdc1ab364
                © 2018

                http://www.springer.com/tdm

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