MCPH1 regulates chromosome condensation and shaping as a composite modulator of condensin II.
MCPH1 regulates chromosome condensation and shaping as a composite modulator of condensin II.
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DOI：
10.1083/jcb.201106141
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发表时间：
2011-09-19
期刊：
影响因子：
--
通讯作者：
Hirano T
中科院分区：
文献类型：
--
作者：
Yamashita D;Shintomi K;Ono T;Gavvovidis I;Schindler D;Neitzel H;Trimborn M;Hirano T
MCPH 1是一种与原发性小头畸形相关的蛋白质，直接调节凝聚素II以调节染色体凝聚和形状。人类MCPH 1（hMCPH 1）的突变导致原发性小头畸形，其特征是大脑尺寸显著减小。有趣的是，hMCPH 1突变患者细胞在G2期显示出独特的细胞表型，包括过早的染色体凝聚（PCC）。为了测试hMCPH 1是否可能直接参与染色体凝聚的调节，如果是的话，如何，我们开发了一个无细胞检测使用非洲爪蟾卵提取物。我们的研究结果表明，一个N-末端结构域的hMCPH 1特异性抑制凝聚素II的行动，通过竞争其染色体结合位点在体外。这种简单而强大的检测方法使我们能够解剖体内引起原发性小头畸形的突变和不同物种之间的进化取代。使用患者细胞的互补试验表明，而N-末端结构域的hMCPH 1是足以拯救PCC表型，其中央域中发挥了辅助作用，在塑造中期染色体的物理相互作用与凝聚素II。因此，hMCPH 1作为一种复合调节剂的凝聚素II调节染色体的凝聚和成型。
MCPH1, a protein linked to primary microcephaly, directly modulates condensin II to regulate chromosome condensation and shape. 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.
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