The roles of RRP15 in nucleolar formation, ribosome biogenesis and checkpoint control in human cells.
The roles of RRP15 in nucleolar formation, ribosome biogenesis and checkpoint control in human cells.
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RRP15 在人类细胞核仁形成、核糖体生物发生和检查点控制中的作用
DOI：
10.18632/oncotarget.14658
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发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Dong Z;Zhu C;Zhan Q;Jiang W
核仁控制核糖体的生物发生，其扰动诱导核仁应激，抑制细胞周期进程并激活检查点反应。在这里，我们研究了核糖体RNA加工蛋白RRP15在人类细胞核核形成、核糖体生物发生、细胞周期进程和检查点控制中的作用。RRP15定位于核仁中，是核仁形成所必需的。与出芽酵母Rrp15p被报道为60s前亚基的组成部分不同，RRP15在40s前和60s前亚基中都有发现，并参与调控rRNA转录和核糖体的生物发生。对RRP15的干扰诱导核核应激，激活RPL5/RPL11/5S rRNA (RP)-Mdm2-p53轴检查点反应，在p53精通的非转化RPE1细胞中阻滞细胞G1-G1/S，而在p53缺乏的HeLa和MCF7肿瘤细胞中不阻滞细胞。相反，p53缺陷的HeLa和MCF7细胞具有rrp15依赖性核核应激，进入s期，s期干扰激活ATR-Chk1- γH2AX轴DNA复制/损伤检查点反应，延迟S-G2/M进展，最终导致细胞死亡。在精通p53的非转化细胞和缺乏p53的肿瘤细胞中，RRP15依赖性核核应激诱导的选择性检查点反应、细胞周期抑制和/或细胞毒性表明，RRP15可能是癌症治疗的潜在靶点。
The nucleolus controls ribosome biogenesis and its perturbation induces nucleolar stress that inhibits cell cycle progression and activates checkpoint responses. Here, we investigate the roles of ribosomal RNA processing protein, RRP15, in nucleolar formation, ribosome biogenesis, cell cycle progression and checkpoint control in human cells. RRP15 is localized in the nucleolus and required for nucleolar formation. In contrast to the budding yeast Rrp15p that was reported as a component of pre-60S subunits, RRP15 is found in both pre-40S and pre-60S subunits and involved in regulating rRNA transcription and ribosome biogenesis. Perturbation of RRP15 induces nucleolar stress that activates RPL5/RPL11/5S rRNA (RP)-Mdm2-p53 axis checkpoint response and arrests cells at G1-G1/S in p53-proficient non-transformed RPE1 cells but not in p53-deficient HeLa and MCF7 tumor cells. Instead, p53-deficient HeLa and MCF7 cells with RRP15-dependent nucleolar stress enter S-phase with S-phase perturbation that activates ATR-Chk1- γH2AX axis DNA replication/damage checkpoint response, delaying S-G2/M progression and, ultimately, causing cell death. The selective checkpoint response, cell cycle inhibition and/or cytotoxicity induced by RRP15-dependent nucleolar stress in p53-proficient non-transformed cells and p53-deficient tumor cells suggest that RRP15 might be a potential target for cancer therapy.
影响因子：
3
作者：
Kundel DW;Stromquist E;Greene AL;Zhdankin O;Regal RR;Rose-Hellekant TA
通讯作者：
Rose-Hellekant TA