Protein Complex of Drosophila ATRX/XNP and HP1a Is Required for the Formation of Pericentric Beta-heterochromatin in Vivo
Protein Complex of Drosophila ATRX/XNP and HP1a Is Required for the Formation of Pericentric Beta-heterochromatin in Vivo
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DOI：
10.1074/jbc.m109.064790
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发表时间：
2010-05-14
影响因子：
4.8
通讯作者：
Fyodorov, Dmitry V.
中科院分区：
文献类型：
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作者：
Emelyanov, Alexander V.;Konev, Alexander Y.;Fyodorov, Dmitry V.
ATRX属于SWI 2/SNF 2-like ATP依赖性核小体重塑分子马达蛋白家族。人类ATRX基因的突变导致一种严重的遗传性疾病，称为X连锁α-地中海贫血精神发育迟滞（ATR-X）综合征。在这里，我们进行生化和遗传分析的黑腹果蝇的直系同源ATRX。果蝇ATRX/XNP基因的功能缺失等位基因是半致死的。果蝇ATRX在整个发育过程中以两种亚型p185和p125表达。ATRX 185和ATRX 125在果蝇胚胎中形成不同的多亚基复合物。ATRX 185复合物包含p185和异染色质蛋白HP 1a。一致地，ATRX 185而不是ATRX 125高度浓缩在幼虫细胞中X染色体的臂间β异染色质中。HP 1a在体外强烈刺激ATRX 185的生化活性。相反，ATRX 185是HP 1a沉积在X染色体臂间β-异染色质中所必需的。ATRX/XNP基因的功能缺失等位基因和不表达p185的突变等位基因是位置效应杂色的强抑制因子。这些结果为果蝇ATRX在体内的基本生物学功能提供了证据，并建立了ATRX作为臂间β-异染色质身份的主要决定因素。
ATRX belongs to the family of SWI2/SNF2-like ATP-dependent nucleosome remodeling molecular motor proteins. Mutations of the human ATRX gene result in a severe genetic disorder termed X-linked alpha-thalassemia mental retardation (ATR-X) syndrome. Here we perform biochemical and genetic analyses of the Drosophila melanogaster ortholog of ATRX. The loss of function allele of the Drosophila ATRX/XNP gene is semilethal. Drosophila ATRX is expressed throughout development in two isoforms, p185 and p125. ATRX185 and ATRX125 form distinct multisubunit complexes in fly embryo. The ATRX185 complex comprises p185 and heterochromatin protein HP1a. Consistently, ATRX185 but not ATRX125 is highly concentrated in pericentric beta-heterochromatin of the X chromosome in larval cells. HP1a strongly stimulates biochemical activities of ATRX185 in vitro. Conversely, ATRX185 is required for HP1a deposition in pericentric beta-heterochromatin of the X chromosome. The loss of function allele of the ATRX/XNP gene and mutant allele that does not express p185 are strong suppressors of position effect variegation. These results provide evidence for essential biological functions of Drosophila ATRX in vivo and establish ATRX as a major determinant of pericentric beta-heterochromatin identity.