MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface
- University of Oxford, United Kingdom
- The Institute of Cancer Research, United Kingdom
- Baylor College of Medicine, United States
- Human Technopole, Italy
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)
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MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interfaceNCBI Gene Expression Omnibus, GSE188988.
Article and author information
Author details
Lothar Schermelleh
Alessandro Vannini
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.
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.
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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