Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II.
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by marked reduction in brain size and mental retardation. Mutations in the gene MCPH1, encoding microcephalin, cause MCPH and a unique cellular phenotype with premature chromosome condensation in early G2 phase and delayed decondensation post mitosis. Here, we show that in MCPH1 patient cells, siRNA-mediated depletions of condensin II subunits lead to a pronounced reduction of cells with the condensation defects in both G1 and G2 phases of the cell cycle. Similar results are obtained when microcephalin and condensin II are simultaneously depleted in HeLa cells. In contrast, depletions of condensin I subunits do not reverse the cellular phenotype. Consistently, condensin I stays in the cytoplasm in the prophase-like cells of MCPH1 patients. Our results offer a molecular explanation for the aberrant chromosome condensation in MCPH1-deficiency and provide additional evidence that condensin I and II are regulated by distinct pathways.
Trimborn
Marc
M
Institut für Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany. marc.trimborn@charite.de
Schindler
Detlev
D
Neitzel
Heidemarie
H
Hirano
Tatsuya
T
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C460645:MCPH1 protein, human; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C108312:condensin complexes; D000251:Adenosine Triphosphatases