Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage.
Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage.
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DOI：
10.1242/jcs.197236
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发表时间：
2017-03-15
影响因子：
4
通讯作者：
Ström L
中科院分区：
文献类型：
--
作者：
Bot C;Pfeiffer A;Giordano F;Manjeera DE;Dantuma NP;Ström L
需要 NIPBL 将粘连蛋白复合物加载到 DNA 上。虽然粘连蛋白的典型作用是将复制的姐妹染色单体耦合在一起直至有丝分裂开始，但它也促进对 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独立机制被招募到 DNA 损伤中，并受到损伤类型的影响。首先，异染色质蛋白 HP1γ（也称为 CBX3）通过 N 末端内相应的 HP1 结合基序将 NIPBL 招募到 DNA 双链断裂 (DSB)。相比之下，C 端 HEAT 重复结构域无法将 NIPBL 募集到 DSB，但独立地将 NIPBL 靶向激光微辐照诱导的 DNA 损伤。每种机制都依赖于 RNF8 和 RNF168 泛素化途径，而 HEAT 重复结构域的招募需要进一步的 ATM 或 ATR 活性。因此，NIPBL 已经进化出对受损 DNA 的复杂反应，该反应受损伤形式的影响，表明 NIPBL 在维持基因组稳定性方面发挥着高度动态的作用。摘要：NIPBL（粘连蛋白装载机）在不同类型的 DNA 损伤处的积累是通过独立的机制发生的。这一发现增强了我们对 NIPBL 在基因组稳定性中高度动态作用的理解。
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. Summary: Accumulation of NIPBL, the cohesin loader, at different types of DNA lesions occurs through independent mechanisms. This finding enhances our understanding of the highly dynamic roles for NIPBL in genome stability.