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MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface
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 exclusiv...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673838/ https://www.ncbi.nlm.nih.gov/pubmed/34850681 http://dx.doi.org/10.7554/eLife.73348 |
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author | Houlard, Martin Cutts, Erin E Shamim, Muhammad S Godwin, Jonathan Weisz, David Presser Aiden, Aviva Lieberman Aiden, Erez Schermelleh, Lothar Vannini, Alessandro Nasmyth, Kim |
author_facet | Houlard, Martin Cutts, Erin E Shamim, Muhammad S Godwin, Jonathan Weisz, David Presser Aiden, Aviva Lieberman Aiden, Erez Schermelleh, Lothar Vannini, Alessandro Nasmyth, Kim |
author_sort | Houlard, Martin |
collection | PubMed |
description | 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 Mcph1 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. |
format | Online Article Text |
id | pubmed-8673838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-86738382021-12-17 MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface Houlard, Martin Cutts, Erin E Shamim, Muhammad S Godwin, Jonathan Weisz, David Presser Aiden, Aviva Lieberman Aiden, Erez Schermelleh, Lothar Vannini, Alessandro Nasmyth, Kim eLife Biochemistry and Chemical Biology 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 Mcph1 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. eLife Sciences Publications, Ltd 2021-12-01 /pmc/articles/PMC8673838/ /pubmed/34850681 http://dx.doi.org/10.7554/eLife.73348 Text en © 2021, Houlard et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Houlard, Martin Cutts, Erin E Shamim, Muhammad S Godwin, Jonathan Weisz, David Presser Aiden, Aviva Lieberman Aiden, Erez Schermelleh, Lothar Vannini, Alessandro Nasmyth, Kim MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title | MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title_full | MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title_fullStr | MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title_full_unstemmed | MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title_short | MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface |
title_sort | mcph1 inhibits condensin ii during interphase by regulating its smc2-kleisin interface |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673838/ https://www.ncbi.nlm.nih.gov/pubmed/34850681 http://dx.doi.org/10.7554/eLife.73348 |
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