Origin of radiation-induced genomic instability

NBS1是隐性遗传性奈亨断裂综合征的相关蛋白，奈亨断裂综合征具有对电离辐射高度敏感、染色体不稳定和易患肿瘤的特点。我们在这里证明了NBS1调控同源重组修复，同源重组缺陷的患者可以存活，但它会导致基因组不稳定和肿瘤发生。目前的研究结果还表明，NBS1通过与组蛋白H2AX相互作用，将MRE11核酸酶招募到双链断裂位点。除了这些相互作用外，NBS1还与WRN（一种加速衰老疾病Werner综合征的蛋白）和FANC（一种隐性遗传性疾病Fancony贫血的蛋白）结合，其特征是对交联DNA损伤高度敏感。尽管它们在响应双链断裂中的作用仍然难以捉摸，但这种修复网络可能有助于DNA损伤后的基因组稳定性。根据表型相似，将奈梅根断裂综合征分为ATM蛋白突变的共济失调毛细血管扩张症（Ataxia telangiec扩张症，A-T）和MRE11缺陷的A-T样疾病。我们的研究结果还表明，NBS1与ATM和mre11在细胞周期检查点相关，但与通过同源重组修复DNA无关。综上所述，这些结果可能揭示了检查点和DNA修复之间的十字路口，而它们必须在暴露于电离辐射后保持基因组的稳定性。

NBS1 is a responsible protein for recessive hereditary disease Nijmegen breakage syndrome, which is characterized by high sensitivity to ionizing radiation, chromosomal instability and predisposition to tumor. We demonstrated here that NBS1 regulates homologous recombination repair and the patients with defect in homologous recombination can survive, while it causes genomic instability and tumorigenesis. Present results also showed that NBS1 recruits MRE11 nuclease to sites of double strand breaks through interaction with histon H2AX. In addition to these interactions, NBS1 also binds to WRN, a protein for accelerated aging disease Werner syndrome, and FANC, a protein for recessive hereditary disease Fancony anemia, which is characterized by high sensitivity to inter-crosslinked DNA damage. Although their role in response to double strand breaks remains elusive, this repair network could contribute to genome stability after generation of DNA damage. On the basis of phenotypic resembles, Nijmegen breakage syndrome is categolized to Ataxia telangiectasia (A-T), which is mutated in ATM protein, and A-T like disorder, which is defective in MRE11. Our results also showed that NBS1 is associated with ATM and MRE11for cell cycle checkpoint but not for DNA repair via homologous recombination. Taken together, these results could shed light on a crossroad between checkpoint and DNA repair, whereas they must associated to maintain genome stability after exposure to ionizing radiation.