MCM2-7-dependent cohesin loading during S phase promotes sister-chromatid cohesion

  1. Ge Zheng
  2. Mohammed Kanchwala
  3. Chao Xing
  4. Hongtao Yu  Is a corresponding author
  1. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
  2. University of Texas Southwestern Medical Center, United States

Abstract

DNA replication transforms cohesin rings dynamically associated with chromatin into the cohesive form to establish sister-chromatid cohesion. Here, we show that, in human cells, cohesin loading onto chromosomes during early S phase requires the replicative helicase MCM2-7 and the kinase DDK. Cohesin and its loader SCC2/4 (NIPBL/MAU2 in humans) associate with DDK and phosphorylated MCM2-7. This binding does not require MCM2-7 activation by CDC45 and GINS, but its persistence on activated MCM2-7 requires fork-stabilizing replisome components. Inactivation of these replisome components impairs cohesin loading and causes interphase cohesion defects. Interfering with Okazaki fragment processing and nucleosome assembly does not impact cohesion. Therefore, MCM2-7-coupled cohesin loading promotes cohesion establishment, which occurs without Okazaki fragment maturation. We propose that the cohesin-loader complex bound to MCM2-7 is mobilized upon helicase activation, transiently held by the replisome, and deposited behind the replication fork to encircle sister chromatids and establish cohesion.

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Author details

  1. Ge Zheng

    Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mohammed Kanchwala

    Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chao Xing

    Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1838-0502
  4. Hongtao Yu

    Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    hongtao.yu@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8861-049X

Funding

Howard Hughes Medical Institute

  • Hongtao Yu

Welch Foundation

  • Hongtao Yu

Cancer Prevention and Research Institute of Texas

  • Hongtao Yu

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

Copyright

© 2018, Zheng 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. Ge Zheng
  2. Mohammed Kanchwala
  3. Chao Xing
  4. Hongtao Yu
(2018)
MCM2-7-dependent cohesin loading during S phase promotes sister-chromatid cohesion
eLife 7:e33920.
https://doi.org/10.7554/eLife.33920

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https://doi.org/10.7554/eLife.33920