Differential requirements for H/ACA ribonucleoprotein components in cell proliferation and response to DNA damage.
Differential requirements for H/ACA ribonucleoprotein components in cell proliferation and response to DNA damage.
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DOI：
10.1007/s00418-015-1359-6
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发表时间：
2015-12
影响因子：
2.3
通讯作者：
Alawi F
中科院分区：
文献类型：
--
作者：
Lin P;Mobasher ME;Hakakian Y;Kakarla V;Naseem AF;Ziai H;Alawi F
H/ACA核糖核蛋白（RNP）由四种保守蛋白质dyskerin、NHP 2、NOP 10和GAR 1以及一种功能特异的非编码H/ACA RNA组成。H/ACA RNP有助于端粒酶的组装和稳定，以及新生核糖体RNA和剪接体RNA的转录后加工。然而，很少有人知道这四种蛋白质在其他生物过程中的协调作用。如本文所述，我们观察到细胞增殖中对蛋白质的不同需求，并鉴定了这些因子在调节特异性DNA损伤生物标志物中的可能依赖性。特别是，GAR 1表达上调后，暴露于所有形式的遗传毒性压力测试。相比之下，其他蛋白质的水平降低或不受影响。只有GAR 1显示出改变的亚细胞定位与转移后，从核仁到核质紫外线-C照射和阿霉素治疗。瞬时siRNA介导的GAR 1和dyskerin的耗竭抑制了细胞增殖，而NHP 2或NOP 10的缺失则没有影响。最后，dyskerin、GAR 1、NHP 2和NOP 10的丢失分别限制了DNA损伤生物标志物的积累。然而，个人的反应取决于所遭受的具体损害类型。一般来说，GAR 1的缺失对测试的生物标志物具有最大的抑制作用。由于对遗传毒性应激的特异性反应、每种蛋白质对细胞增殖的贡献以及DNA损伤生物标志物的激活不相等，这表明至少一些蛋白质，最显著的是GAR 1，可能独立于它们在H/ACA RNP复合物中的各自作用而潜在地发挥作用。
H/ACA ribonucleoproteins (RNPs) are comprised of four conserved proteins, dyskerin, NHP2, NOP10, and GAR1, and a function-specifying, noncoding H/ACA RNA. H/ACA RNPs contribute to telomerase assembly and stabilization, and posttranscriptional processing of nascent ribosomal RNA and spliceosomal RNA. However, very little is known about the coordinated action of the four proteins in other biologic processes. As described herein, we observed a differential requirement for the proteins in cell proliferation and identified a possible reliance for these factors in regulation of specific DNA damage biomarkers. In particular, GAR1 expression was upregulated following exposure to all forms of genotoxic stress tested. In contrast, levels of the other proteins were either reduced or unaffected. Only GAR1 showed an altered subcellular localization with a shift from the nucleolus to the nucleoplasm after ultraviolet-C irradiation and doxorubicin treatments. Transient siRNA-mediated depletion of GAR1 and dyskerin arrested cell proliferation, whereas loss of either NHP2 or NOP10 had no effect. Finally, loss of dyskerin, GAR1, NHP2, and NOP10, respectively, limited the accumulation of DNA damage biomarkers. However, the individual responses were dependent upon the specific type of damage incurred. In general, loss of GAR1 had the most suppressive effect on the biomarkers tested. Since the specific responses to genotoxic stress, the contribution of each protein to cell proliferation, and the activation of DNA damage biomarkers were not equivalent, this suggests the possibility that at least some of the proteins, most notably GAR1, may potentially function independently of their respective roles within H/ACA RNP complexes.
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DOI：
10.1083/jcb.200601105
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Darzacq X;Kittur N;Roy S;Shav-Tal Y;Singer RH;Meier UT
通讯作者：
Meier UT
影响因子：
4.8
作者：
Ding, Wen-Xing;Ni, Hong-Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
影响因子：
3.7
作者：
Alawi F;Lin P
通讯作者：
Lin P
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
11.4
作者：
Bellodi, Cristian;Kopmar, Noam;Ruggero, Davide
通讯作者：
Ruggero, Davide