A DYRK1B-dependent pathway suppresses rDNA transcription in response to DNA damage.
A DYRK1B-dependent pathway suppresses rDNA transcription in response to DNA damage.
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DOI：
10.1093/nar/gkaa1290
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发表时间：
2021-02-22
影响因子：
14.9
通讯作者：
Huen MSY
中科院分区：
文献类型：
--
作者：
Dong C;An L;Yu CH;Huen MSY
核糖体基因座处的DNA双链断裂（DSB）触发核糖体DNA（rDNA）转录的抑制和广泛的核仁重组，包括核仁帽的形成，其中rDNA DSB与典型的DSB信号传导和修复因子接合。虽然这些核仁反应是维持rDNA稳定性的基础，但驱动这些事件的分子组分仍有待确定。在这里，我们报告说，完全抑制rRNA的合成需要DYRK1B激酶，核仁DSB反应，可以从ATM介导的DSB信号事件在核仁周边解偶联。事实上，通过将DSB靶向到rDNA阵列上，我们发现DYRK1B的化学抑制或遗传失活导致持续的核仁转录。激光微辐射穿过细胞核后，DYRK1B不仅表现出强大的核仁积累，我们还进一步表明DYRK1B是rDNA DSB修复和rDNA拷贝数维持所需的，并且DYRK1B失活的细胞对rDNA阵列上诱导的DSB超敏。总之，我们的研究结果不仅确定DYRK1B作为协调DSB修复和rDNA转录活性的关键信号中间体，而且还支持在核仁内操作以保持rDNA完整性的专门DSB反应的想法。
DNA double-strand breaks (DSBs) at ribosomal gene loci trigger inhibition of ribosomal DNA (rDNA) transcription and extensive nucleolar reorganization, including the formation of nucleolar caps where rDNA DSBs engage with canonical DSB signaling and repair factors. While these nucleolar responses underlie maintenance of rDNA stability, the molecular components that drive each of these events remain to be defined. Here we report that full suppression of rRNA synthesis requires the DYRK1B kinase, a nucleolar DSB response that can be uncoupled from ATM-mediated DSB signaling events at the nucleolar periphery. Indeed, by targeting DSBs onto rDNA arrays, we uncovered that chemical inhibition or genetic inactivation of DYRK1B led to sustained nucleolar transcription. Not only does DYRK1B exhibit robust nucleolar accumulation following laser micro-irradiation across cell nuclei, we further showed that DYRK1B is required for rDNA DSB repair and rDNA copy number maintenance, and that DYRK1B-inactivated cells are hypersensitised to DSBs induced at the rDNA arrays. Together, our findings not only identify DYRK1B as a key signaling intermediate that coordinates DSB repair and rDNA transcriptional activities, but also support the idea of specialised DSB responses that operate within the nucleolus to preserve rDNA integrity.
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影响因子：
10.5
作者：
Marnef, Aline;Finoux, Anne-Laure;Legube, Gaelle
通讯作者：
Legube, Gaelle
影响因子：
8.8
作者：
Harding SM;Boiarsky JA;Greenberg RA
通讯作者：
Greenberg RA
影响因子：
14.9
作者：
Larsen DH;Stucki M
通讯作者：
Stucki M
影响因子：
10.5
作者：
van Sluis M;McStay B
通讯作者：
McStay B
DOI：
10.1083/jcb.201109100
发表时间：
2012-04-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Poulsen M;Lukas C;Lukas J;Bekker-Jensen S;Mailand N
通讯作者：
Mailand N