Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability
Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability
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DOI：
10.1074/jbc.m212484200
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发表时间：
2003-04-25
影响因子：
4.8
通讯作者：
Carpenter, PB
中科院分区：
文献类型：
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作者：
Morales, JC;Xia, ZF;Carpenter, PB
p53 结合蛋白-1 (53BP1) 因 DNA 损伤而被磷酸化，并与 Mrell 和磷酸化组蛋白 2A 变体 γ-H2AX 一起快速重新定位到 DNA 损伤的推定位点。 53BP1 与 BRCA1 肿瘤抑制因子相关，小干扰 RNA 的敲低实验揭示了该蛋白在检查点对 DNA 损伤的反应中的作用。通过生成 m53BP1 (m53BP1(tr/tr)) 缺陷小鼠，我们创建了动物模型以进一步探索其在体内的生化和遗传作用。我们发现 m53BP1(tr/tr) 动物生长迟缓，并表现出各种免疫缺陷，包括胸腺大小和 T 细胞计数的特定减少。与响应 DNA 损伤的作用一致，我们发现 m53BP1(tr/tr) 小鼠对电离辐射 (gamma-IR) 敏感，并且来自这些动物的细胞表现出与 DNA 修复缺陷一致的染色体异常。因此，53BP1 是 DNA 损伤反应中的关键元件，在维持基因组稳定性方面发挥着不可或缺的作用。
p53-binding protein-1 (53BP1) is phosphorylated in response to DNA damage and rapidly relocalizes to presumptive sites of DNA damage along with Mrell and the phosphorylated histone 2A variant, gamma-H2AX. 53BP1 associates with the BRCA1 tumor suppressor, and knockdown experiments with small interfering RNA have revealed a role for the protein in the checkpoint response to DNA damage. By generating mice defective in m53BP1 (m53BP1(tr/tr)), we have created an animal model to further explore its biochemical and genetic roles in vivo. We find that m53BP1(tr/tr) animals are growth-retarded and show various immune deficiencies including a specific reduction in thymus size and T cell count. Consistent with a role in responding to DNA damage, we find that m53BP1(tr/tr) mice are sensitive to ionizing radiation (gamma-IR), and cells from these animals exhibit chromosomal abnormalities consistent with defects in DNA repair. Thus, 53BP1 is a critical element in the DNA damage response and plays an integral role in maintaining genomic stability.