Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks

Abstract

Replicative helicases in all cell types are hexameric rings that unwind DNA by steric exclusion in which the helicase encircles the tracking strand only and excludes the other strand from the ring. This mode of translocation allows helicases to bypass blocks on the strand that is excluded from the central channel. Unlike other replicative helicases, eukaryotic CMG helicase partially encircles duplex DNA at a forked junction and is stopped by a block on the non-tracking (lagging) strand. This report demonstrates that Mcm10, an essential replication protein unique to eukaryotes, binds CMG and greatly stimulates its helicase activity in vitro. Most significantly, Mcm10 enables CMG and the replisome to bypass blocks on the non-tracking DNA strand. We demonstrate that bypass occurs without displacement of the blocks and therefore Mcm10 must isomerize the CMG-DNA complex to achieve the bypass function.

Article and author information

Author details

  1. Lance D Langston

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2736-9284
  2. Ryan Mayle

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Grant D Schauer

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Olga Yurieva

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniel Zhang

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nina Y Yao

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Roxana E Georgescu

    The Rockefeller University, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1882-2358
  8. Mike E O'Donnell

    The Rockefeller University, New York City, United States
    For correspondence
    odonnel@mail.rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9002-4214

Funding

Howard Hughes Medical Institute

  • Lance D Langston
  • Ryan Mayle
  • Olga Yurieva
  • Roxana E Georgescu
  • Mike E O'Donnell

National Institutes of Health (GM38839)

  • Lance D Langston
  • Ryan Mayle
  • Grant D Schauer
  • Olga Yurieva
  • Daniel Zhang
  • Nina Y Yao
  • Roxana E Georgescu
  • Mike E O'Donnell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael R Botchan, University of California, Berkeley, United States

Publication history

  1. Received: June 1, 2017
  2. Accepted: September 3, 2017
  3. Accepted Manuscript published: September 4, 2017 (version 1)
  4. Version of Record published: September 14, 2017 (version 2)

Copyright

© 2017, Langston et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lance D Langston
  2. Ryan Mayle
  3. Grant D Schauer
  4. Olga Yurieva
  5. Daniel Zhang
  6. Nina Y Yao
  7. Roxana E Georgescu
  8. Mike E O'Donnell
(2017)
Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks
eLife 6:e29118.
https://doi.org/10.7554/eLife.29118
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