Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Department of Biochemistry and Molecular Biology, Excellent Talent Project, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
Institute of Medical Technology, University of Tampere, Tampere University Hospital, Biokatu 8, 33014, Tampere, Finland.
Cell Death Differ. 2018 Sep;25(9):1625-1637. doi: 10.1038/s41418-018-0068-9. Epub 2018 Feb 19.
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.
在此，Tudor-SN 被鉴定为一种与 DNA 损伤反应（DDR）相关的蛋白质，它在 DDR 的早期阶段发挥着重要作用。X 射线或激光照射可以通过与 PARP-1 的相互作用，以依赖多聚（ADP-核糖）化的方式将 Tudor-SN 募集到 DNA 损伤部位。此外，我们说明 Tudor-SN 的 SN 结构域介导了这两种蛋白质的结合。积累的 Tudor-SN 进一步募集 SMARCA5（ATP 依赖的染色质重塑酶）和 GCN5（组蛋白乙酰转移酶）到 DNA 损伤部位，导致染色质松弛，从而激活 ATM 激酶和下游的 DNA 修复信号通路，促进细胞存活。一致地，Tudor-SN 的功能丧失减弱了 SMARCA5、GCN5 和组蛋白 H3 的乙酰化（acH3）在 DNA 断裂部位的富集，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 蛋白在不同的肿瘤中高度表达，它可能参与癌症治疗的放射抵抗。
