The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity
The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity
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DOI：
10.1093/hmg/ddn116
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
Jabs, Ethylin Wang
中科院分区：
文献类型：
--
作者：
Gordillo, Miriam;Vega, Hugo;Jabs, Ethylin Wang
Roberts综合征/SC短肢畸形（RBS）是一种常染色体隐性遗传疾病，伴有生长迟缓、颅面畸形和肢体缩小。RBS中的细胞改变包括着丝粒周围异染色质区域和Y染色体长臂处缺乏凝聚力、生长能力降低以及对DNA损伤剂的超敏反应。RBS是由ESCO 2突变引起的，ESCO 2编码一种属于高度保守的乙酰转移酶Eco 1/Ctf 7家族的蛋白质，参与调节姐妹染色单体的凝聚力。我们发现了10个新的突变，将已知的ESCO 2突变数量扩大到26个。我们观察到这些突变导致乙酰转移酶结构域的完全或部分丧失，除了在该结构域中发生的唯一错义突变（c.1615T > G，W539 G）。为了研究RBS的潜在机制，我们分析了ESCO 2突变对酶活性和细胞表型的影响。我们发现ESCO 2 W539 G导致自乙酰转移酶活性的丧失。由该突变产生的细胞表型导致内聚缺陷、增殖能力降低和丝裂霉素C敏感性，与由移码和无义突变产生的那些等同，所述移码和无义突变与mRNA水平降低和蛋白质缺失相关。我们发现RBS细胞系的增殖能力下降与细胞死亡有关，但与细胞周期持续时间增加无关，这可能是RBS中短肢畸形和腭裂发展的一个因素。总之，我们提供了第一个证据表明，乙酰转移酶活性的损失有助于RBS的发病机制，强调Eco 1 p蛋白家族的酶活性的重要作用。
Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. We identified 10 new mutations expanding the number to 26 known ESCO2 mutations. We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T > G, W539G). To investigate the mechanism underlying RBS, we analyzed ESCO2 mutations for their effect on enzymatic activity and cellular phenotype. We found that ESCO2 W539G results in loss of autoacetyltransferase activity. The cellular phenotype produced by this mutation causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS. In summary, we provide the first evidence that loss of acetyltransferase activity contributes to the pathogenesis of RBS, underscoring the essential role of the enzymatic activity of the Eco1p family of proteins.