NOP53 undergoes liquid-liquid phase separation and promotes tumor radio-resistance.
NOP53 undergoes liquid-liquid phase separation and promotes tumor radio-resistance.
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NOP53发生液-液相分离并促进肿瘤放射抗性
DOI：
10.1038/s41420-022-01226-8
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发表时间：
2022-10-31
影响因子：
7
通讯作者：
Fan, Xin-Juan
中科院分区：
文献类型：
--
作者：
Shi, Jie;Chen, Si-Ying;Shen, Xiao-Ting;Yin, Xin-Ke;Zhao, Wan-Wen;Bai, Shao-Mei;Feng, Wei-Xing;Feng, Li-Li;Qin, Caolitao;Zheng, Jian;Wang, Yun-Long;Fan, Xin-Juan
异常DNA损伤响应轴（Aberrant DNA damage response， DDR）仍然是肿瘤放射抵抗的主要分子机制。我们最近表征了液-液相分离（LLPS）是DDR的重要机制，并确定了几个关键的DDR因子作为潜在的LLPS蛋白，包括核蕊蛋白NOP53。在本研究中，我们发现NOP53在体内和体外形成高度浓缩的液滴，具有邻近凝聚物融合、光漂白后荧光恢复迅速、对1,6-己二醇敏感等液体性质。此外，内在无序区1 （IDR1）是NOP53相分离所必需的。此外，富含多价精氨酸的线性基序（M-R基序）在NOP53中丰富，是其核仁定位所必需的，但在NOP53的LLPS中是必不可少的。功能上，NOP53沉默抑制肿瘤细胞生长，并显著使结直肠癌（CRC）细胞对放疗敏感。机械上，NOP53负调控放疗或不放疗的CRC细胞中的p53通路。重要的是，来自临床样本的数据证实了NOP53表达与肿瘤放射耐药之间的相关性。综上所述，这些结果表明NOP53在放射耐药中的重要作用，并为肿瘤放射增敏提供了一个潜在的靶点。
Aberrant DNA damage response (DDR) axis remains the major molecular mechanism for tumor radio-resistance. We recently characterized liquid-liquid phase separation (LLPS) as an essential mechanism of DDR, and identified several key DDR factors as potential LLPS proteins, including nucleolar protein NOP53. In this study, we found that NOP53 formed highly concentrated droplets in vivo and in vitro, which had liquid-like properties including the fusion of adjacent condensates, rapid fluorescence recovery after photobleaching and the sensitivity to 1,6-hexanediol. Moreover, the intrinsically disordered region 1 (IDR1) is required for NOP53 phase separation. In addition, multivalent-arginine-rich linear motifs (M-R motifs), which are enriched in NOP53, were essential for its nucleolar localization, but were dispensable for the LLPS of NOP53. Functionally, NOP53 silencing diminished tumor cell growth, and significantly sensitized colorectal cancer (CRC) cells to radiotherapy. Mechanically, NOP53 negatively regulated p53 pathway in CRC cells treated with or without radiation. Importantly, data from clinical samples confirmed a correlation between NOP53 expression and tumor radio-resistance. Together, these results indicate an important role of NOP53 in radio-resistance, and provide a potential target for tumor radio-sensitization.
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DOI：
10.1038/nrclinonc.2015.120
发表时间：
2015-09
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Schaue D;McBride WH
通讯作者：
McBride WH
影响因子：
16.6
作者：
Mitrea DM;Cika JA;Stanley CB;Nourse A;Onuchic PL;Banerjee PR;Phillips AH;Park CG;Deniz AA;Kriwacki RW
通讯作者：
Kriwacki RW
影响因子：
64.8
作者：
Ries, Ryan J.;Zaccara, Sara;Jaffrey, Samie R.
通讯作者：
Jaffrey, Samie R.
影响因子：
14.9
作者：
Bagatelli FFM;de Luna Vitorino FN;da Cunha JPC;Oliveira CC
通讯作者：
Oliveira CC
影响因子：
7.3
作者：
Lafita-Navarro, M. Carmen;Conacci-Sorrell, Maralice
通讯作者：
Conacci-Sorrell, Maralice