An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele
An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele
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DOI：
10.1038/86920
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发表时间：
2001-04-01
期刊：
影响因子：
30.8
通讯作者：
Petrini, JHJ
中科院分区：
文献类型：
--
作者：
Maser, RS;Zinkel, R;Petrini, JHJ
奈梅亨断裂综合征（Nijmegen breakage syndrome，NBS）是一种罕见的染色体不稳定综合征，与癌症易感性、放射敏感性和放射抗性DNA合成-S期检查点缺陷相关，导致DNA损伤后不能抑制DNA复制起点。大约90%的NBS患者是657 del 5等位基因纯合子（1，2），这是一种NBS 1截短突变，导致密码子219处提前终止。由于编码NBS 1结合伴侣的MRE 11和RAD 50中的无效突变在脊椎动物中是致命的（3-5），而小鼠NBS 1无效突变体是不可存活的（6），我们测试了NBS 1 657 del 5突变是亚型缺陷的假设。我们发现，NBS细胞含有预测的26 kD氨基末端蛋白片段，NBS 1（p26）和一个70 kD的NBS 1蛋白（NBS 1（p70））缺乏天然的N末端。NBSP 26蛋白与MRE 11复合物没有物理关联，而p70物质与之物理关联。NBS 1（p70）通过使用由657 del 5移码产生的开放阅读框在NBS 1 mRNA内的内部翻译起始产生。我们提出，共同的NBS 1等位基因编码的部分功能蛋白，减少NBS表型的严重程度。
Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity and radioresistant DNA synthesis-S phase checkpoint deficiency, which results in the failure to suppress DNA replication origins following DNA damage. Approximately 90% of NBS patients are homozygous for the 657del5 allele(1,2), a truncating mutation of NBS1 that causes premature termination at codon 219. Because null mutations in MRE11 and RAD50, which encode binding partners of NBS1, are lethal in vertebrates(3-5), and mouse Nbs1-null mutants are inviable(6), we tested the hypothesis that the NBS1 657del5 mutation was a hypomorphic defect. We showed that NBS cells contain the predicted 26-kD amino-terminal protein fragment, NBS1(p26) and a 70-kD NBS1 protein (NBS1(p70)) lacking the native N terminus. The NBSp26 protein is not physically associated with the MRE11 complex, whereas the p70 species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS1 mRNA using an open reading frame generated by the 657del5 frameshift. We propose that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype.