Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.
EMBO J. 2012 Oct 17;31(20):4045-56. doi: 10.1038/emboj.2012.247. Epub 2012 Aug 31.
Human single-stranded DNA-binding protein 1 (hSSB1), encoded by OBFC2B, was recently characterized as an essential factor for the initiation of DNA damage checkpoints and the maintenance of genomic stability. Here, we report that loss of Obfc2b in mice results in perinatal lethality characterized by growth delay and skeletal abnormalities. These abnormalities are associated with accumulation of γH2ax, apoptosis and defective pre-cartilage condensation, which is essential for normal bone formation. However, deficiency of Obfc2b does not affect the initiation of DNA damage checkpoints, Atm activation, or the maintenance of genomic stability in B lymphocytes and primary fibroblasts. Loss of Obfc2b results in increased expression of its homologue Obfc2a (hSSB2). In contrast to Obfc2b deficiency, depletion of Obfc2a in fibroblasts results in impaired proliferation, accumulation of γH2ax and increased genomic instability. Thus, the hSSB1 orthologue Obfc2b has a unique function during embryogenesis limited to cell types that contribute to bone formation. While being dispensable in most other cell lineages, its absence leads to a compensatory increase in Obfc2a protein, a homologue required for the maintenance of genomic integrity.
人类单链 DNA 结合蛋白 1（hSSB1），由 OBFC2B 编码，最近被确定为启动 DNA 损伤检查点和维持基因组稳定性的必需因素。在这里，我们报告说，小鼠中 Obfc2b 的缺失导致围产期致死，其特征是生长迟缓和骨骼异常。这些异常与 γH2ax 的积累、凋亡和软骨前凝聚的缺陷有关，而软骨前凝聚对于正常的骨骼形成是必不可少的。然而，Obfc2b 的缺乏并不影响 DNA 损伤检查点的启动、Atm 的激活或 B 淋巴细胞和原代成纤维细胞中基因组稳定性的维持。Obfc2b 的缺失导致其同源物 Obfc2a（hSSB2）的表达增加。与 Obfc2b 缺乏相反，成纤维细胞中 Obfc2a 的耗竭导致增殖受损、γH2ax 的积累增加和基因组不稳定性增加。因此，hSSB1 同源物 Obfc2b 在胚胎发生过程中具有独特的功能，仅限于参与骨骼形成的细胞类型。虽然在大多数其他细胞谱系中是可有可无的，但它的缺失会导致 Obfc2a 蛋白的代偿性增加，而 Obfc2a 蛋白是维持基因组完整性所必需的。
