核仁RNA聚合酶II促进核糖体生物发生

在该研究中，研究人员发现人核仁中的RNA聚合酶II（Pol II）在编码rRNA的基因附近诱导其表达。在神经退行性相关酶senataxin的辅助下，Pol II在核仁核糖体RNA（rRNA）基因两侧的基因间隔基上产生了一个包含三链核酸结构（称为R环）的屏蔽。该屏蔽层可防止Pol I产生有义的基因间非编码RNA（sincRNA），该RNA会破坏核仁组织和rRNA表达。这些破坏性sincRNA可以通过蛋白质RNaseH1、eGFP和dCas9的实验系统（我们称为“红色激光”）被Pol II抑制、senataxin丧失、尤因肉瘤或与基因座相关R环的阻抑而释放出来。

该研究揭示了核仁Pol-II依赖的机制，其可促进核糖体生物发生，通过非编码RNA识别疾病相关的核仁破坏，并建立针对基因座的R环调控。该发现修订了主要RNA聚合酶之间分工的理论，并确定核仁Pol II是蛋白质合成和核组织的主要因子，对健康和疾病的研究具有潜在影响。

据了解，蛋白质是由核糖体翻译产生的，核糖体是由蛋白质和RNA组成的大分子复合物，它们在核仁内组装。现有模型表明，RNA聚合酶I和III（Pol I和Pol III）是唯一直接介导核糖体的组成成分rRNA表达的酶。

附：英文原文

Title: Nucleolar RNA polymerase II drives ribosome biogenesis

Author: Karan J. Abraham, Negin Khosraviani, Janet N. Y. Chan, Aparna Gorthi, Anas Samman, Dorothy Y. Zhao, Miling Wang, Michael Bokros, Elva Vidya, Lauren A. Ostrowski, Roxanne Oshidari, Violena Pietrobon, Parasvi S. Patel, Arash Algouneh, Rajat Singhania, Yupeng Liu, V. Talya Yerlici, Daniel D. De Carvalho, Michael Ohh, Brendan C. Dickson, Razq Hakem, Jack F. Greenblatt, Stephen Lee, Alexander J. R. Bishop, Karim Mekhail

Issue&Volume: 2020-07-15

Abstract: Proteins are manufactured by ribosomes—macromolecular complexes of protein and RNA molecules that are assembled within major nuclear compartments called nucleoli1,2. Existing models suggest that RNA polymerases I and III (Pol I and Pol III) are the only enzymes that directly mediate the expression of the ribosomal RNA (rRNA) components of ribosomes. Here we show, however, that RNA polymerase II (Pol II) inside human nucleoli operates near genes encoding rRNAs to drive their expression. Pol II, assisted by the neurodegeneration-associated enzyme senataxin, generates a shield comprising triplex nucleic acid structures known as R-loops at intergenic spacers flanking nucleolar rRNA genes. The shield prevents Pol I from producing sense intergenic noncoding RNAs (sincRNAs) that can disrupt nucleolar organization and rRNA expression. These disruptive sincRNAs can be unleashed by Pol II inhibition, senataxin loss, Ewing sarcoma or locus-associated R-loop repression through an experimental system involving the proteins RNaseH1, eGFP and dCas9 (which we refer to as ‘red laser’). We reveal a nucleolar Pol-II-dependent mechanism that drives ribosome biogenesis, identify disease-associated disruption of nucleoli by noncoding RNAs, and establish locus-targeted R-loop modulation. Our findings revise theories of labour division between the major RNA polymerases, and identify nucleolar Pol II as a major factor in protein synthesis and nuclear organization, with potential implications for health and disease.

DOI: 10.1038/s41586-020-2497-0

Source: https://www.nature.com/articles/s41586-020-2497-0