Oncoprotein Tudor-SN is a key determinant providing survival advantage under DNA damaging stress
Oncoprotein Tudor-SN is a key determinant providing survival advantage under DNA damaging stress
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癌蛋白 Tudor-SN 是在 DNA 损伤压力下提供生存优势的关键决定因素。
DOI：
10.1038/s41418-018-0068-9
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发表时间：
2018-09-01
影响因子：
12.4
通讯作者：
Yang, Jie
中科院分区：
文献类型：
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作者：
Fu, Xiao;Zhang, Chunyan;Yang, Jie
本研究发现Tudor-SN是一种DNA损伤反应（DDR）相关蛋白，在DDR早期发挥重要作用。x射线或激光照射可通过与PARP-1相互作用，以聚（adp -核糖基）依赖的方式引起Tudor-SN在DNA损伤部位的积累。此外，我们还发现Tudor-SN的SN结构域介导了这两种蛋白的结合。积累的Tudor-SN进一步将SMARCA5 （atp依赖性染色质重塑剂）和GCN5（组蛋白乙酰转移酶）招募到DNA损伤位点，导致染色质松弛，从而激活ATM激酶和下游DNA修复信号通路，促进细胞存活。与此一致的是，Tudor-SN的功能缺失减弱了SMARCA5、GCN5的富集和DNA断裂位点组蛋白H3 （acH3）的乙酰化，并消除了染色质松弛；结果，细胞表现出DNA修复和细胞存活缺陷。由于Tudor-SN蛋白在不同肿瘤中均有高表达，可能与肿瘤治疗的放射耐药有关。
Herein, Tudor-SN was identified as a DNA damage response (DDR)-related protein that plays important roles in the early stage of DDR. X-ray or laser irradiation could evoke the accumulation of Tudor-SN to DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner via interaction with PARP-1. Additionally, we illustrated that the SN domain of Tudor-SN mediated the association of these two proteins. The accumulated Tudor-SN further recruited SMARCA5 (ATP-dependent chromatin remodeller) and GCN5 (histone acetyltransferase) to DNA damage sites, resulting in chromatin relaxation, and consequently activating the ATM kinase and downstream DNA repair signalling pathways to promote cell survival. Consistently, the loss-of-function of Tudor-SN attenuated the enrichment of SMARCA5, GCN5 and acetylation of histone H3 (acH3) at DNA break sites and abolished chromatin relaxation; as a result, the cells exhibited DNA repair and cell survival deficiency. As Tudor-SN protein is highly expressed in different tumours, it is likely to be involved in the radioresistance of cancer treatment.