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

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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.

Data availability

The following data sets were generated

1. Zheng G
2. Kanchwala M
3. Xing C
4. Yu H
(2018) MCM2-7-dependent cohesin loading during S phase promotes sister-chromatid cohesion
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE112018).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112028

Article and author information

Author details

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.
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.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-1838-0502
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.

"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

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.