Nijmegen breakage syndrome and functions of the responsible protein, NBS1
Nijmegen breakage syndrome and functions of the responsible protein, NBS1
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DOI：
10.1159/000092508
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Komatsu, K.
中科院分区：
文献类型：
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作者：
Antoccia, A.;Kobayashi, J.;Komatsu, K.
奈亨断裂综合征（NBS）是一种罕见的隐性遗传疾病，以鸟类样面部外观、早期发育迟缓、先天性小头畸形、免疫缺陷和恶性肿瘤高发为特征。NBS属于所谓的染色体不稳定综合征；事实上，NBS细胞表现出自发的染色体畸变，并且对DNA双链断裂诱导剂（如电离辐射）高度敏感。致病基因NBS1位于人类染色体8q21上。该疾病似乎在东欧和中欧人群中普遍存在，其中90%以上的患者是创始突变657del5的纯合子，导致该蛋白的截断变体。NBS1在c端与MRE11/RAD50核酸酶形成多聚体复合物，并通过直接结合组蛋白H2AX在DNA损伤位点附近保留或招募它们，而组蛋白H2AX在DNA损伤时被pi3激酶家族磷酸化，如ATM。此后，nbs1复合体主要通过同源重组修复在脊椎动物中重新连接双链断裂。NBS细胞在s期检查点的激活上也存在缺陷。我们在此回顾NBS的一些细胞和分子方面，这可能有助于疾病的临床症状。
Nijmegen breakage syndrome (NBS) is a rare recessive genetic disorder, characterized by bird-like facial appearance, early growth retardation, congenital microcephaly, immunodeficiency and high frequency of malignancies. NBS belongs to the so-called chromosome instability syndromes; in fact, NBS cells display spontaneous chromosomal aberrations and are hypersensitive to DNA double-strand break-inducing agents, such as ionizing radiations. NBS1, the gene underlying the disease, is located on human chromosome 8q21. The disease appears to be prevalent in the Eastern and Central European population where more than 90% of patients are homozygous for the founder mutation 657del5 leading to a truncated variant of the protein. NBS1 forms a multimeric complex with MRE11/RAD50 nuclease at the C-terminus and retains or recruits them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by PI3-kinase family, such as ATM, in response to DNA damage. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. NBS cells also show to be defective in the activation of intra-S phase checkpoint. We review here some cellular and molecular aspects of NBS, which might contribute to the clinical symptoms of the disease.