TY - JOUR T1 - MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface JF - bioRxiv DO - 10.1101/2021.07.20.453033 SP - 2021.07.20.453033 AU - Martin Houlard AU - Erin E. Cutts AU - Muhammad S. Shamim AU - Jonathan Godwin AU - David Weisz AU - Aviva Presser Aiden AU - Erez Lieberman Aiden AU - Lothar Schermelleh AU - Alessandro Vannini AU - Kim Nasmyth Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/20/2021.07.20.453033.abstract N2 - 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 LE 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 from patients carrying 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 SMC complexes must be tightly regulated to adjust both the chromatid’s structure and their segregation.Competing Interest StatementThe authors have declared no competing interest.HAWKHEAT repeat protein associated with the kleisinLEloop extrusionPLCprophase like cellsSLiMshort linear motifTADstopologically associating domainsCryo EMcryo electron microscopyAFMatomic force microscopyGVBDgerminal vesicle break down ER -