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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\u2019s 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\n                    <jats:italic>Mcph1<\/jats:italic>\n                    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\u2019s NCAPG2 subunit. MCPH1\u2019s ability to block condensin II\u2019s 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.73348","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T08:01:04Z","timestamp":1638345664000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73348","source":"Crossref","is-referenced-by-count":53,"title":["MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6780-6939","authenticated-orcid":true,"given":"Martin","family":"Houlard","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3290-4293","authenticated-orcid":true,"given":"Erin E","family":"Cutts","sequence":"first","affiliation":[{"name":"Division of Structural Biology, The Institute of Cancer Research","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad S","family":"Shamim","sequence":"additional","affiliation":[{"name":"The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston, United States"]},{"name":"Medical Scientist Training Program, Baylor College of Medicine, Department of Bioengineering, Rice University","place":["Houston, United States"]},{"name":"Center for Theoretical Biological Physics, Rice University","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Godwin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Weisz","sequence":"additional","affiliation":[{"name":"The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston, United States"]},{"name":"Center for Theoretical Biological Physics, Rice University","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviva","family":"Presser Aiden","sequence":"additional","affiliation":[{"name":"The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston, United States"]},{"name":"Center for Theoretical Biological Physics, Rice University","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erez","family":"Lieberman Aiden","sequence":"additional","affiliation":[{"name":"The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston, United States"]},{"name":"Center for Theoretical Biological Physics, Rice University","place":["Houston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1612-9699","authenticated-orcid":true,"given":"Lothar","family":"Schermelleh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7212-5425","authenticated-orcid":true,"given":"Alessandro","family":"Vannini","sequence":"additional","affiliation":[{"name":"Division of Structural Biology, The Institute of Cancer Research","place":["London, United Kingdom"]},{"name":"Human Technopole","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Nasmyth","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1101\/gad.2016411","article-title":"The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II","volume":"25","author":"Abe","year":"2011","journal-title":"Genes & Development"},{"key":"bib2","article-title":"juicer","volume-title":"GitHub","author":"Aiden Lab","year":"2020","unstructured":"Aiden Lab. 2020a. juicer. 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