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 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.
Highlights
The segregation of sister DNAs during mitosis requires that they are first disentangled and organised into individual sister chromatids before being pulled in opposite directions by the mitotic spindle upon the dissolution of sister chromatid cohesion by separase
We show that loss of MCPH1 induces a prophase-like organisation of chromatin during G1 and G2 but not during S phase, and that this depends on condensin II
We demonstrate that MCPH1 instead regulates the organisation of chromosomal DNA through the binding of condensin II’s NCAPG2 subunit by a conserved short linear motif (SLiM) situated within its central domain
Summary
The segregation of sister DNAs during mitosis requires that they are first disentangled and organised into individual sister chromatids before being pulled in opposite directions by the mitotic spindle upon the dissolution of sister chromatid cohesion by separase. Chromatid formation during mitosis and sister chromatid cohesion necessary for bi-orientation are mediated by highly related structural maintenance of chromosomes (SMC)-kleisin complexes, namely condensin and cohesin respectively In both cases, the activity of their ring-like SMC-kleisin trimers is regulated by large hook-shaped proteins composed of tandem HEAT repeats, known as HAWKs (HEAT repeat proteins associated with kleisins) (Yatskevich et al., 2019). LE mediated by cohesin is halted or at least retarded at specific sequences bound by CTCF, and the processivity of the complex is reduced by WAPL which induces cohesin’s dissociation from chromatin, albeit only infrequently every 10-20 min (Gerlich et al, 2006; Hansen et al, 2017; Wutz et al., 2020) No such site-specific DNA binding proteins are known to regulate condensin
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