Houlard, M. orcid.org/0000-0001-6780-6939, Cutts, E.E. orcid.org/0000-0003-3290-4293, Shamim, M.S. et al. (7 more authors) (2021) MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface. eLife, 10. e73348. ISSN 2050-084X
Abstract
Dramatic change in chromosomal DNA morphology between interphase and mitosis is a 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. We show that deletion of <jats:italic>Mcph1</jats:italic> in mouse embryonic stem cells unleashes an activity of condensin II that triggers formation of compact chromosomes in G1 and G2 phases, accompanied by enhanced mixing of A and B chromatin compartments, and 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. MCPH1’s ability to block condensin II’s association with chromatin is abrogated by the fusion of SMC2 with NCAPH2, hence may work by a mechanism similar to cohesin. 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | biochemistry; cell biology; cell cycle; chemical biology; chromosome; cohesin; condensation; condensin; human; microcephalin; mouse; Animals; Cell Cycle Proteins; Cytoskeletal Proteins; Embryonic Stem Cells; Gene Expression Regulation; Interphase; Metabolic Networks and Pathways; Mice |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Jan 2025 10:44 |
Last Modified: | 23 Jan 2025 10:44 |
Published Version: | https://doi.org/10.7554/elife.73348 |
Status: | Published |
Publisher: | eLife Sciences Publications, Ltd |
Refereed: | Yes |
Identification Number: | 10.7554/elife.73348 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:221962 |