Williams Bret R, Mirzoeva Olga K, Morgan William F, Lin Junyu, Dunnick Wesley, Petrini John H J
Laboratory of Genetics, University of Wisconsin Medical School, Madison, WI, USA.
Curr Biol. 2002 Apr 16;12(8):648-53. doi: 10.1016/s0960-9822(02)00763-7.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and predisposition to hematopoietic malignancy. The clinical and cellular phenotypes of NBS substantially overlap those of ataxia-telangiectasia (A-T). NBS is caused by mutation of the NBS1 gene, which encodes a member of the Mre11 complex, a trimeric protein complex also containing Mre11 and Rad50. Several lines of evidence indicate that the ataxia-telangiectasia mutated (ATM) kinase and the Mre11 complex functionally interact. Both NBS and A-T cells exhibit ionizing radiation (IR) sensitivity and defects in the intra S phase checkpoint, resulting in radioresistant DNA synthesis (RDS)-the failure to suppress DNA replication origin firing after IR exposure. NBS1 is phosphorylated by ATM in response to IR, and this event is required for activation of the intra S phase checkpoint (the RDS checkpoint). We derived a murine model of NBS, the Nbs1(DeltaB/DeltaB) mouse. Nbs1(DeltaB/DeltaB) cells are phenotypically identical to those established from NBS patients. The Nbs1(DeltaB) allele was synthetically lethal with ATM deficiency. We propose that the ATM-Mre11 complex DNA damage response pathway is essential and that ATM or the Mre11 complex serves as a nexus to additional components of the pathway.
奈梅亨断裂综合征（NBS）是一种罕见的常染色体隐性疾病，其特征为小头畸形、免疫缺陷以及易患造血系统恶性肿瘤。NBS的临床和细胞表型与共济失调毛细血管扩张症（A-T）有很大重叠。NBS由NBS1基因突变引起，该基因编码Mre11复合物的一个成员，Mre11复合物是一种三聚体蛋白复合物，还包含Mre11和Rad50。多项证据表明，共济失调毛细血管扩张症突变（ATM）激酶与Mre11复合物在功能上相互作用。NBS和A-T细胞均表现出对电离辐射（IR）敏感以及S期内检查点缺陷，导致抗辐射DNA合成（RDS）——即IR照射后无法抑制DNA复制起点的激活。NBS1在IR作用下被ATM磷酸化，这一事件是激活S期内检查点（RDS检查点）所必需的。我们构建了NBS的小鼠模型，即Nbs1(DeltaB/DeltaB)小鼠。Nbs1(DeltaB/DeltaB)细胞在表型上与从NBS患者建立的细胞相同。Nbs1(DeltaB)等位基因与ATM缺陷具有合成致死性。我们提出，ATM-Mre11复合物DNA损伤反应途径至关重要，且ATM或Mre11复合物是该途径其他成分的连接点。
