Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model.

Proceedings of the National Academy of Sciences of the United States of America
Yasunori NoguchiHuilin Li

Abstract

During replication initiation, the core component of the helicase-the Mcm2-7 hexamer-is loaded on origin DNA as a double hexamer (DH). The two ring-shaped hexamers are staggered, leading to a kinked axial channel. How the origin DNA interacts with the axial channel is not understood, but the interaction could provide key insights into Mcm2-7 function and regulation. Here, we report the cryo-EM structure of the Mcm2-7 DH on dsDNA and show that the DNA is zigzagged inside the central channel. Several of the Mcm subunit DNA-binding loops, such as the oligosaccharide-oligonucleotide loops, helix 2 insertion loops, and presensor 1 (PS1) loops, are well defined, and many of them interact extensively with the DNA. The PS1 loops of Mcm 3, 4, 6, and 7, but not 2 and 5, engage the lagging strand with an approximate step size of one base per subunit. Staggered coupling of the two opposing hexamers positions the DNA right in front of the two Mcm2-Mcm5 gates, with each strand being pressed against one gate. The architecture suggests that lagging-strand extrusion initiates in the middle of the DH that is composed of the zinc finger domains of both hexamers. To convert the Mcm2-7 DH structure into the Mcm2-7 hexamer structure found in the act...Continue Reading

References

May 1, 1993·Molecular and Cellular Biology·A L JacksonR A Sclafani
Jun 5, 2002·Annual Review of Biochemistry·Stephen P Bell, Anindya Dutta
Feb 1, 2005·FEBS Letters·Bruce Stillman
Jul 9, 2005·Trends in Biochemical Sciences·Tatsuro S TakahashiJohannes C Walter
Aug 24, 2005·Nature Structural & Molecular Biology·Adam T McGeochStephen D Bell
May 9, 2006·Proceedings of the National Academy of Sciences of the United States of America·Elizabeth R Jenkinson, James P J Chong
May 13, 2006·Annual Review of Biophysics and Biomolecular Structure·Jan P Erzberger, James M Berger
Jun 27, 2006·Proceedings of the National Academy of Sciences of the United States of America·Stephen E MoyerMichael R Botchan
Jul 21, 2006·Nature·Eric J Enemark, Leemor Joshua-Tor
Sep 22, 2007·The Journal of Biological Chemistry·Eli RothenbergTaekjip Ha
Mar 11, 2008·Current Opinion in Structural Biology·Eric J Enemark, Leemor Joshua-Tor
Jul 30, 2008·Molecular and Cellular Biology·Matthew L BochmanAnthony Schwacha
Aug 21, 2009·The Journal of Biological Chemistry·Irina Bruck, Daniel Kaplan
Sep 22, 2009·Current Opinion in Cell Biology·Dirk Remus, John F X Diffley
Sep 29, 2009·Critical Reviews in Biochemistry and Molecular Biology·Alessandro Costa, Silvia Onesti
Nov 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Cecile EvrinChristian Speck
Feb 4, 2010·Molecular Cell·Ivar IlvesMichael R Botchan
Dec 22, 2010·Molecular Cell·Michael Botchan, James Berger
Feb 2, 2011·Current Opinion in Structural Biology·Artem Y LyubimovJames M Berger
May 21, 2011·Nucleic Acids Research·Brent E SteadMegan J Davey
Jan 31, 2012·Current Biology : CB·George WataseMasato T Kanemaki
Aug 25, 2012·Sub-cellular Biochemistry·Huilin Li, Bruce Stillman
Aug 25, 2012·Sub-cellular Biochemistry·Sriram Vijayraghavan, Anthony Schwacha
Aug 25, 2012·Sub-cellular Biochemistry·Wenyue DuBrandt F Eichman
Nov 20, 2012·Advances in Experimental Medicine and Biology·Barbara Medagli, Silvia Onesti
Mar 12, 2013·Nature·Jordi FrigolaJohn F X Diffley
Jul 16, 2013·Nature Structural & Molecular Biology·Jingchuan SunHuilin Li
Mar 29, 2014·Science·Alexey AmuntsV Ramakrishnan
Aug 5, 2014·Molecular Cell·Gideon CosterJohn F X Diffley

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Citations

Feb 7, 2018·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Huilin Li, Michael E O'Donnell
Feb 1, 2019·Genes·Leticia Koch Lerner, Julian E Sale
Mar 1, 2018·Nature·Max E DouglasJohn F X Diffley
Mar 27, 2019·PloS One·Ramon Y Rios-MoralesStephen P Bell
Jul 17, 2019·Nature Communications·Martin MeagherEric J Enemark
Jul 10, 2019·ELife·Lance D Langston, Michael E O'Donnell
Nov 22, 2019·Nature·Thomas C R MillerAlessandro Costa
May 6, 2020·Biochemical Society Transactions·Jacob S Lewis, Alessandro Costa
Jul 25, 2018·The Journal of Biological Chemistry·Sumeet PoudelMichael Leffak
Jul 28, 2020·Nature Communications·Hazal B KoseHasan Yardimci
Jul 17, 2020·Proceedings of the National Academy of Sciences of the United States of America·Zuanning YuanChristian Speck
Mar 20, 2020·Cell & Bioscience·Wenshuo ZhangQing Li
Apr 14, 2018·Frontiers in Molecular Biosciences·Yeon-Soo Seo, Young-Hoon Kang
Jan 23, 2021·International Journal of Molecular Sciences·Megan Schmit, Anja-Katrin Bielinsky
Feb 6, 2021·Materials·Amna Abdalla Mohammed KhalidLoredana Casalis
May 6, 2020·Molecular Cell·Domagoj BaretićJoseph T P Yeeles
Mar 28, 2021·Nature Communications·Humberto SánchezNynke H Dekker
Jun 9, 2021·Acta Crystallographica. Section F, Structural Biology Communications·Martin MeagherEric J Enemark
Mar 31, 2021·Annual Review of Biochemistry·Ilan AttaliJames M Berger
Aug 19, 2021·Critical Reviews in Biochemistry and Molecular Biology·Amy J Fernandez, James M Berger
Oct 27, 2021·Nature·Michael Jenkyn-BedfordTom D Deegan

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Methods Mentioned

BETA
PCR

Software Mentioned

COOT
PHENIX
Chimera
CTFFIND4
PyMOL
MotionCorr
RELION

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