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J Cell Biol. 2011 Sep 19;194(6):841-54. doi: 10.1083/jcb.201106141. Epub 2011 Sep 12.

MCPH1 regulates chromosome condensation and shaping as a composite modulator of condensin II.

Author information

1
Chromosome Dynamics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan.

Abstract

Mutations in human MCPH1 (hMCPH1) cause primary microcephaly, which is characterized by a marked reduction of brain size. Interestingly, hMCPH1 mutant patient cells display unique cellular phenotypes, including premature chromosome condensation (PCC), in G2 phase. To test whether hMCPH1 might directly participate in the regulation of chromosome condensation and, if so, how, we developed a cell-free assay using Xenopus laevis egg extracts. Our results demonstrate that an N-terminal domain of hMCPH1 specifically inhibits the action of condensin II by competing for its chromosomal binding sites in vitro. This simple and powerful assay allows us to dissect mutations causing primary microcephaly in vivo and evolutionary substitutions among different species. A complementation assay using patient cells revealed that, whereas the N-terminal domain of hMCPH1 is sufficient to rescue the PCC phenotype, its central domain plays an auxiliary role in shaping metaphase chromosomes by physically interacting with condensin II. Thus, hMCPH1 acts as a composite modulator of condensin II to regulate chromosome condensation and shaping.

PMID:
21911480
PMCID:
PMC3207293
DOI:
10.1083/jcb.201106141
[Indexed for MEDLINE]
Free PMC Article

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