The Drosophila Mre11/Rad50 complex is required to prevent both telomeric fusion and chromosome breakage
The Drosophila Mre11/Rad50 complex is required to prevent both telomeric fusion and chromosome breakage
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DOI：
10.1016/j.cub.2004.07.019
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发表时间：
2004-08-10
期刊：
影响因子：
9.2
通讯作者：
Gatti, M
中科院分区：
文献类型：
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作者：
Ciapponi, L;Cenci, G;Gatti, M
MRN复合体由两个进化保守的组分Mre11和Rad50以及第三个不太保守的组分Nbs1/Xrs2组成[1,2]。除了响应DNA双链断裂的各种功能外，该复合体还介导端粒维持，包括同源重组、非同源末端连接（NHEJ）和DNA损伤检查点的激活。Mre11基因突变导致人类共济失调-毛细血管扩张样疾病（ATDL）[1,2]。在这里，我们发现果蝇mre11和rad50基因的零突变导致端粒融合和染色体断裂。此外，我们证明这些突变在端粒盖帽和有丝分裂染色体完整性所需的相同上位组中。使用针对Rad50的抗体，我们发现该蛋白均匀分布在有丝分裂染色体上，并且Rad50在缺乏其结合伙伴Mre11时是不稳定的。为了确定rad50和mre11在端粒保护中的作用，我们对突变体染色体制备体进行了HP1和HOAP的免疫染色，这两种蛋白可以保护果蝇端粒免受融合[3,4]。细胞学分析显示，rad50和mre11突变显著减少端粒中HOAP和HP1的积累。这表明MRN复合体通过促进HOAP和HP1在染色体末端的募集来保护果蝇的端粒。
The MRN complex consists of the two evolutionarily conserved components Mre11 and Rad50 and the third less-conserved component Nbs1/Xrs2 [1, 2]. This complex mediates telomere maintenance in addition to a variety of functions in response to DNA double-strand breaks, including homologous recombination, nonhomologous end joining (NHEJ), and activation of DNA damage checkpoints. Mutations in the Mre11 gene cause the human ataxia-telangiectasia-like disorder (ATDL) [1, 2]. Here, we show that null mutations in the Drosophila mre11 and rad50 genes cause both telomeric fusion and chromosome breakage. Moreover, we demonstrate that these mutations are in the same epistasis group required for telomere capping and mitotic chromosome integrity. Using an antibody against Rad50, we show that this protein is uniformly distributed along mitotic chromosomes, and that Rad50 is unstable in the absence of its binding partner Mre11. To define the roles of rad50 and mre11 in telomere protection, mutant chromosome preparations were immunostained for both HP1 and HOAP, two proteins that protect Drosophila telomeres from fusion [3, 4]. Cytological analysis revealed that mutations in rad50 and mre11 drastically reduce accumulation of HOAP and HP1 at telomeres. This suggests that the MRN complex protects Drosophila, telomeres by facilitating recruitment of HOAP and HP1 at chromosome ends.