1. Biochemistry and Chemical Biology
  2. Cell Biology

MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface

  1. Martin Houlard
  2. Erin E Cutts
  3. Muhammad S Shamim
  4. Jonathan Godwin
  5. David Weisz
  6. Aviva Presser Aiden
  7. Erez Lieberman-Aiden
  8. Lothar Schermelleh
  9. Kim Nasmyth
  10. Alessandro Vannini  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. The Institute of Cancer Research, United Kingdom
  3. Baylor College of Medicine, United States
  4. Human Technopole, Italy
https://doi.org/10.7554/eLife.73348
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Cite this article
  1. Martin Houlard
  2. Erin E Cutts
  3. Muhammad S Shamim
  4. Jonathan Godwin
  5. David Weisz
  6. Aviva Presser Aiden
  7. Erez Lieberman-Aiden
  8. Lothar Schermelleh
  9. Kim Nasmyth
  10. Alessandro Vannini
(2021)
MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface
eLife 10:e73348.
https://doi.org/10.7554/eLife.73348
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Abstract

The dramatic change in morphology of chromosomal DNAs between interphase and mitosis is one of the defining features of the eukaryotic cell cycle. Two types of enzymes, namely cohesin and condensin confer the topology of chromosomal DNA by extruding DNA loops. While condensin normally configures chromosomes exclusively during mitosis, cohesin does so during interphase. The processivity of cohesin’s loop extrusion during interphase is limited by a regulatory factor called WAPL, which induces cohesin to dissociate from chromosomes via a mechanism that requires dissociation of its kleisin from the neck of SMC3. We show here that a related mechanism may be responsible for blocking condensin II from acting during interphase. Cells derived from patients affected by microcephaly caused by mutations in the MCPH1 gene undergo premature chromosome condensation but it has never been established for certain whether MCPH1 regulates condensin II directly. We show that deletion of Mcph1 in mouse embryonic stem cells unleashes an activity of condensin II that triggers formation of compact chromosomes in G1 and G2 phases, which is accompanied by enhanced mixing of A and B chromatin compartments, and that this occurs even in the absence of CDK1 activity. Crucially, inhibition of condensin II by MCPH1 depends on the binding of a short linear motif within MCPH1 to condensin II's NCAPG2 subunit. We show that the activities of both Cohesin and Condensin II may be restricted during interphase by similar types of mechanisms as MCPH1's ability to block condensin II's association with chromatin is abrogated by the fusion of SMC2 with NCAPH2. Remarkably, in the absence of both WAPL and MCPH1, cohesin and condensin II transform chromosomal DNAs of G2 cells into chromosomes with a solenoidal axis showing that both cohesin and condensin must be tightly regulated to adjust the structure of chromatids for their successful segregation.

Data availability

HiC sequencing data has been deposited in GEO. (accession number: GSE188988)

The following data sets were generated

Article and author information

Author details

  1. Martin Houlard

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Erin E Cutts

    Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3290-4293

  3. Muhammad S Shamim

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Jonathan Godwin

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. David Weisz

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Aviva Presser Aiden

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Erez Lieberman-Aiden

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Lothar Schermelleh

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1612-9699

  9. Kim Nasmyth

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  10. Alessandro Vannini

    Structural Biology Research Centre, Human Technopole, Milan, Italy
    For correspondence
    alessandro.vannini@fht.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7212-5425

Funding

Wellcome Trust (107935/Z/15/Z)

  • Martin Houlard
  • Jonathan Godwin
  • Kim Nasmyth

McNair Medical Institute Scholar Award

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375)

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

US-Israel Binational Science Foundation Award (2019276)

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

Behavioral Plasticity Research Institute (NSF DBI-2021795)

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

NSF Physics Frontiers Center Award (NSF PHY-2019745)

  • Muhammad S Shamim
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden
  • Lothar Schermelleh

NIH CEGS Award (RM1HG011016-01A1)

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

European Research Council (294401)

  • Martin Houlard
  • Jonathan Godwin
  • Kim Nasmyth

Cancer Research UK (26747)

  • Martin Houlard
  • Jonathan Godwin
  • Kim Nasmyth

Wellcome Trust (107457/Z/15/Z)

  • Lothar Schermelleh

Wellcome Trust (091911)

  • Lothar Schermelleh

Paul and Daisy Soros Foundation

  • Muhammad S Shamim

Cancer Research UK (CR-UK C47547/A21536)

  • Erin E Cutts
  • Alessandro Vannini

Wellcome Trust (200818/Z/16/Z)

  • Erin E Cutts
  • Alessandro Vannini

Welch Foundation (Q-1866)

  • Muhammad S Shamim
  • David Weisz
  • Aviva Presser Aiden
  • Erez Lieberman-Aiden

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

Reviewing Editor

  1. Adèle L Marston, University of Edinburgh, United Kingdom

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the University of Arizona. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Minnesota (Permit Number: 27-2956). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Version history

  1. Preprint posted: July 20, 2021 (view preprint)
  2. Received: August 25, 2021
  3. Accepted: November 8, 2021
  4. Accepted Manuscript published: December 1, 2021 (version 1)
  5. Version of Record published: December 14, 2021 (version 2)

Copyright

© 2021, Houlard 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. Martin Houlard
  2. Erin E Cutts
  3. Muhammad S Shamim
  4. Jonathan Godwin
  5. David Weisz
  6. Aviva Presser Aiden
  7. Erez Lieberman-Aiden
  8. Lothar Schermelleh
  9. Kim Nasmyth
  10. Alessandro Vannini
(2021)
MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface
eLife 10:e73348.
https://doi.org/10.7554/eLife.73348

Share this article

https://doi.org/10.7554/eLife.73348

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