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| Status |
Public on Nov 19, 2021 |
| Title |
MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
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 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 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 cohesin and condensin must be tightly regulated to adjust the structure of chromatids for their successful segregation.
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| Overall design |
Analysis of the impact of Mcph1 deletion on genome architecture
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| Contributor(s) |
Houlard M, Cutts EE, Shamim MS, Godwin J, Weisz D, Schermelleh L, Aiden AP, Aiden EL, Vannini A, Nasmyth K |
| Citation(s) |
34850681 |
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| Submission date |
Nov 16, 2021 |
| Last update date |
Jan 07, 2022 |
| Contact name |
Muhammad Saad Shamim |
| E-mail(s) |
shamim@rice.edu
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| Organization name |
Rice University
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| Department |
Bioengineering
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| Lab |
Aiden
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| Street address |
6100 Main Street
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| City |
Houston |
| State/province |
Texas |
| ZIP/Postal code |
77005-1827 |
| Country |
USA |
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| Platforms (1) |
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| Samples (2) |
| GSM5692829 |
Wild type E14 embryonic stem cells |
| GSM5692830 |
Mcph1 deleted homozygous E14 embryonic stem cells |
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| Relations |
| BioProject |
PRJNA780949 |
| SRA |
SRP346438 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE188988_RAW.tar |
3.9 Gb |
(http)(custom) |
TAR (of HIC) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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