Origin of radiation-induced genomic instability

NBS1是隐性遗传病Nijmegen断裂综合征的主要致病蛋白，具有对电离辐射高度敏感、染色体不稳定和肿瘤易感性等特点。我们在这里证明了NBS1调节同源重组修复，同源重组缺陷的患者可以存活，同时它导致基因组不稳定和肿瘤的发生。目前的结果还表明，NBS1通过与组蛋白H_2AX的相互作用，将Mre11核酸酶招募到双链断裂的位置。除了这些相互作用外，NBS1还与WRN和FANC结合，WRN是一种引起加速衰老疾病Werner综合征的蛋白质，FANC是一种隐性遗传病Fancony贫血的蛋白质，其特征是对交叉连接的DNA损伤高度敏感。尽管它们在双链断裂反应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。根据表型相似性，奈梅根断裂综合征可分为ATM蛋白突变的毛细血管扩张性共济失调(A-T)和Mre11缺陷的A-T样障碍。我们的结果还表明，NBS1与ATM和MRE11的细胞周期检查点相关，但与通过同源重组进行DNA修复无关。综上所述，这些结果可能会揭示检查点和DNA修复之间的十字路口，而它们必须关联起来，以在暴露于电离辐射后保持基因组的稳定。

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.