Bot Christopher, Pfeiffer Annika, Giordano Fosco, Manjeera Dharani E, Dantuma Nico P, Ström Lena
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden
J Cell Sci. 2017 Mar 15;130(6):1134-1146. doi: 10.1242/jcs.197236. Epub 2017 Feb 6.
NIPBL is required to load the cohesin complex on to DNA. While the canonical role of cohesin is to couple replicated sister chromatids together until the onset of mitosis, it also promotes tolerance to DNA damage. Here, we show that NIPBL is recruited to DNA damage throughout the cell cycle via independent mechanisms, influenced by type of damage. First, the heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus. By contrast, the C-terminal HEAT repeat domain is unable to recruit NIPBL to DSBs but independently targets NIPBL to laser microirradiation-induced DNA damage. Each mechanism is dependent on the RNF8 and RNF168 ubiquitylation pathway, while the recruitment of the HEAT repeat domain requires further ATM or ATR activity. Thus, NIPBL has evolved a sophisticated response to damaged DNA that is influenced by the form of damage, suggesting a highly dynamic role for NIPBL in maintaining genomic stability.
NIPBL 是将黏连蛋白复合物加载到 DNA 上所必需的。虽然黏连蛋白的典型作用是在有丝分裂开始前将复制后的姐妹染色单体连接在一起，但它也能提高对 DNA 损伤的耐受性。在这里，我们表明，NIPBL 在整个细胞周期中通过受损伤类型影响的独立机制被招募到 DNA 损伤部位。首先，异染色质蛋白 HP1γ（也称为 CBX3）通过 N 端内相应的 HP1 结合基序将 NIPBL 招募到 DNA 双链断裂（DSB）处。相比之下，C 端 HEAT 重复结构域无法将 NIPBL 招募到 DSB 处，但能独立地将 NIPBL 靶向激光微照射诱导的 DNA 损伤部位。每种机制都依赖于 RNF8 和 RNF168 泛素化途径，而 HEAT 重复结构域的招募则需要进一步的 ATM 或 ATR 活性。因此，NIPBL 对受损 DNA 进化出了一种复杂的反应，这种反应受损伤形式的影响，这表明 NIPBL 在维持基因组稳定性方面具有高度动态的作用。
