The mechanism of eukaryotic CMG helicase activation

Nature
Max E DouglasJohn F X Diffley

Abstract

The initiation of eukaryotic DNA replication occurs in two discrete stages: first, the minichromosome maintenance (MCM) complex assembles as a head-to-head double hexamer that encircles duplex replication origin DNA during G1 phase; then, 'firing factors' convert each double hexamer into two active Cdc45-MCM-GINS helicases (CMG) during S phase. This second stage requires separation of the two origin DNA strands and remodelling of the double hexamer so that each MCM hexamer encircles a single DNA strand. Here we show that the MCM complex, which hydrolyses ATP during double-hexamer formation, remains stably bound to ADP in the double hexamer. Firing factors trigger ADP release, and subsequent ATP binding promotes stable CMG assembly. CMG assembly is accompanied by initial DNA untwisting and separation of the double hexamer into two discrete but inactive CMG helicases. Mcm10, together with ATP hydrolysis, then triggers further DNA untwisting and helicase activation. After activation, the two CMG helicases translocate in an 'N terminus-first' direction, and in doing so pass each other within the origin; this requires that each helicase is bound entirely to single-stranded DNA. Our experiments elucidate the mechanism of eukaryotic r...Continue Reading

References

Feb 11, 1975·Biochemistry·T S Hsieh, J C Wang
Nov 15, 1983·Journal of Molecular Biology·D Shore, R L Baldwin
Nov 15, 1983·Journal of Molecular Biology·D Shore, R L Baldwin
Jan 1, 1996·Journal of Structural Biology·M van HeelM Schatz
Jun 5, 2003·Journal of Structural Biology·Joseph A Mindell, Nikolaus Grigorieff
Aug 24, 2005·Nature Structural & Molecular Biology·Adam T McGeochStephen D Bell
Jul 25, 2006·Journal of Structural Biology·Guang TangSteven J Ludtke
Dec 11, 2007·The Journal of Biological Chemistry·Patrick D RobertsonBrandt F Eichman
Feb 4, 2010·Molecular Cell·Ivar IlvesMichael R Botchan
Oct 4, 2011·Nature·Karl E DuderstadtJames M Berger
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
Jul 7, 2014·Nature Structural & Molecular Biology·Roxana E GeorgescuMike E O'Donnell
Aug 5, 2014·Molecular Cell·Gideon CosterJohn F X Diffley
Aug 5, 2014·Molecular Cell·Sukhyun KangStephen P Bell
Mar 6, 2015·Nature·Joseph T P YeelesJohn F X Diffley
Jul 30, 2015·Nature·Ningning LiNing Gao
Nov 3, 2015·Nature Structural & Molecular Biology·Jingchuan SunMichael E O'Donnell
Feb 19, 2016·Nature Communications·Ferdos Abid AliAlessandro Costa
Jul 8, 2016·Genetics·Stephen P Bell, Karim Labib
Jan 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Roxana GeorgescuMichael E O'Donnell
Mar 9, 2017·Genes & Development·Marko LõokeStephen P Bell
Apr 5, 2017·Proceedings of the National Academy of Sciences of the United States of America·Jin Chuan ZhouAlessandro Costa
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Yasunori NoguchiHuilin Li
Dec 23, 2017·Nature Communications·Ferdos Abid AliAlessandro Costa

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Citations

Oct 30, 2018·Genes & Genetic Systems·Yukio Ishimi
Feb 1, 2019·Genes·Leticia Koch Lerner, Julian E Sale
Mar 27, 2019·PloS One·Ramon Y Rios-MoralesStephen P Bell
Mar 9, 2019·Genes·Dominik Boos, Pedro Ferreira
Jul 17, 2019·Nature Communications·Martin MeagherEric J Enemark
Nov 28, 2018·The EMBO Journal·Saša ŠvikovićJulian E Sale
Sep 4, 2019·Nature Reviews. Molecular Cell Biology·Claire MarchalDavid M Gilbert
Jul 10, 2019·ELife·Lance D Langston, Michael E O'Donnell
Nov 16, 2019·Cellular and Molecular Life Sciences : CMLS·Lu LiuHuiqiang Lou
Oct 26, 2018·Applied Immunohistochemistry & Molecular Morphology : AIMM·Satu LuhtalaJorma Isola
May 6, 2020·Biochemical Society Transactions·Jacob S Lewis, Alessandro Costa
Jun 4, 2020·Biochemical Society Transactions·Sara Priego Moreno, Agnieszka Gambus
Sep 5, 2020·Critical Reviews in Biochemistry and Molecular Biology·Thomas A Guilliam, Joseph T P Yeeles
Jun 7, 2020·Annual Review of Microbiology·Mark D Greci, Stephen D Bell
Jan 2, 2019·Nature Structural & Molecular Biology·Yu-Hung ChenDuncan J Smith
May 16, 2019·Nature Communications·Daniel R BurnhamHasan Yardimci
Apr 2, 2020·Nature Cell Biology·Kathleen R Stewart-MorganAnja Groth
Jul 25, 2018·The Journal of Biological Chemistry·Sumeet PoudelMichael Leffak
Jan 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ryan MayleMichael E O'Donnell
Jul 3, 2020·Nature Reviews. Molecular Cell Biology·Matteo BertiMassimo Lopes
Apr 29, 2020·Nature Structural & Molecular Biology·Sujan Devbhandari, Dirk Remus
Jul 28, 2020·Nature Communications·Hazal B KoseHasan Yardimci
Sep 19, 2020·Genes & Development·Emily LowJohannes C Walter
Feb 21, 2021·Scientific Reports·Pedro FerreiraDominik Boos
Feb 23, 2021·Trends in Cell Biology·Ann Schirin MirsanayeNiels Mailand

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