細胞中的RNA降解，是調控蛋白質表現與RNA品質管制的重要機制。許多參與RNA降解的核酸水解酶在不同物種間有高度的保守性。探討這些核酸水解酶參與RNA降解的分子機制，可以讓我們更深入了解這些核酸水解酶，如何可以降解特定不同長度和結構的RNA，以及它們的為何會喪失活性而導致各種疾病。本研究探討兩個參與RNA降解的核酸水解外切酶，分別為大腸桿菌的RNase R (Section 1) 與人類的Rexo2 (Section 2) 。
RNase R為RNase II蛋白質家族的一員，可以降解單股RNA，以及帶有三端懸垂的雙股RNA。我們解析了大腸桿菌RNase R (87-725胺基酸區間) 的蛋白質晶體結構，解析度為1.85 Å。藉由比較RNase R與其同源的其他蛋白結構，我們發現一個位於RNB活性域的"錐子"區域，由三個α螺旋所構成，可能參與RNA解旋。我們製作了"錐子"區域的置換與移除的突變蛋白酶，我們發現這些突變會使RNase R喪失其解旋雙股RNA的能力，但不影響水解單股RNA的能力。根據我們的實驗結果，我們提出RNase R解旋與降解具有二級結構RNA的分子機制，解釋了這個外切酶如何經由其RNB區來移除RNA三端的核甘酸，並同時利用其錐子區來解開雙股RNA，達成降解雙股RNA的功效。
Rexo2為人類粒線體中的蛋白，屬於DEDDh蛋白家族的一員，同樣在不同物種間具有高度保守性。Rexo2具有分解小片段RNA (<5個寡核甘酸)的活性，我們的實驗結果顯示Rexo2可降解小片段RNA與DNA，對小片段RNA具有最高度的降解活性。同時，我們解析了三個解析度為1.8-2.2 Å 的Rexo2與單股RNA或是DNA結合的晶體結構。結構顯示，Rexo2主要與RNA和DNA的三端末兩個鹼基，透過π-π作用結合，故而解釋了為何Rexo2對小片段RNA具有有較高的降解活性。此研究並提出了Rexo2如何將小片段RNA降解成單核甘酸的分子機制，提供了Rexo2參與細胞RNA回收機制的重要資訊。綜合以上的研究，本篇論文探討了兩個參與RNA降解的核酸水解外切酶，他們獨特的RNA辨識與降解的分子機制。透過這些核酸水解酶作用於不同片段、不同結構的RNA，細胞得以有效率地進行RNA降解的程序。

RNA turnover pathways play key roles in protein expression regulation and RNA quality control. Many ribonucleases participating in the RNA turnover pathways are conserved among different species in all kingdoms of life. Understanding the molecular mechanisms of these ribonucleases could allow us to gain a better understanding of how the RNAs with various lengths and structures are degraded, and how the defects of these ribonucleases could lead to human diseases. This study focuses on two 3ʹ-to-5ʹ exoribonucleases, bacterial RNase R and human RNA exoribonuclease 2 (Rexo2), that target to different types of RNA and are involved in RNA turnover in E. coli and human mitochondria, respectively.
RNase R belongs to the RNase II protein family, capable of degrading single-stranded and double-stranded RNA with a 3ʹ overhang. We reported the first crystal structure of E. coli RNase R (residues 87-725) at a resolution of 1.85 Å. By comparing the structure with its homologs, we suggested a “wedge” region in the RNB domain that could participate in duplex RNA unwinding. We also generated RNase R mutants by truncating or replacing the tri-helix wedge region, and these mutants completely lost the RNA unwinding activity but with retained exoribonuclease activity for degrading single-stranded RNA. A model was proposed based on our results suggesting how RNase R binds and unwinds RNA by the wedge region and cleaves RNA by the RNB domain in a highly processive manner to coordinate its activity in degrading structural RNA with a 3ʹ overhang.
Rexo2 is an evolutionarily conserved 3ʹ-to-5ʹ DEDDh-family exonuclease in human mitochondria, but in contrast to RNase R, it primarily degrades RNA of less than five nucleotides (nanoRNA). Here, we show that Rexo2 preferentially binds and degrades both small RNA and DNA oligonucleotides in the presence of Mg2+ ions, but it has the highest degrading activity for nanoRNA. We also reported three crystal structures of Rexo2 in complex with single-stranded RNA and DNA at the resolutions of 1.8-2.2 Å. Our structures show that Rexo2 binds mainly with the last two 3ʹ-end nucleobases of substrates by hydrophobic and π-π stacking interactions, explaining its preference in binding and degrading small oligonucleotides. Our results thus explain how Rexo2 degrades small RNA into nucleoside monophosphates and play an important role in RNA salvage pathways in human mitochondria. Altogether this thesis reveals the distinct RNA recognition and degrading mechanisms for two typical 3ʹ-to-5ʹ exoribonucleases, RNase R and Rexo2, in RNA turnover. Bulk mRNAs are thus degraded efficiently by the cooperative efforts of various ribonucleases in prokaryotes and eukaryotes.

摘要....................2
Abstract....................3
Chapter 1 RNA decay pathways in bacteria and human mitochondria....................8
RNA decay pathways in bacteria....................8
RNA decay pathways in human mitochondria....................8
Chapter 2 Structural basis of RNA unwinding and degradation by RNase R....................10
RNase R is a conserved exoribonuclease in the RNase II protein family....................10
RNase R is a unique 3′-to-5′ exoribonuclease possessing both RNA unwinding and degrading activities....................10
RNase R plays an important role in cell growth and survival in E. coli....................11
RNase R unwinds RNA duplex by thermal breathing of the substrate during degradation and translocation....................11
Materials and methods....................13
Expression vector construction....................13
Protein expression and purification....................14
Crystallization and structure determination....................14
RNase activity assays....................15
RNA binding by fluorescence polarization assays....................16
Helicase assay....................16
Results....................17
RNase R degrades duplex RNA with a 3' overhang....................17
Crystal structure of RNase R ΔHTH-K....................18
Two RNA-binding channels were found in RNase R....................19
Hydrolysis mechanism of RNase R....................20
The tri-helix region in the RNB domain is the “wedge” for RNA unwinding....................21
Discussion....................22
Two open RNA-binding channels are identified in the apo-RNase R structure....................22
A tri-helix wedge region in the RNB domain is important in RNA unwinding....................23
Two RNA unwinding and degradation models for RNase R....................24
Chapter 3 Structural insights into nanoRNA degradation by human Rexo2....................25
Rexo2 is a DEDDh-family 3ʹ-to-5ʹ exoribonuclease in mitochondria....................25
Rexo2 degrades nanoRNAs of less than five nucleotides....................26
Materials and Methods....................27
Cloning, protein expression and purification....................27
RNA and DNA degradation assays....................28
RNA and DNA binding assays....................28
Crystallization and structural determination....................29
Results....................30
Rexo2 preferentially binds and degrades small RNAs into mononucleotides....................30
Crystal structures of Rexo2-RNA and Rexo2-DNA complexes....................32
Rexo2 interacts with the 3ʹ-end di-nucleotide bases by π-π stacking interactions....................34
Two-Mg-ion catalytic mechanism of Rexo2....................34
Discussion....................35
Rexo2 plays an essential role in RNA metabolism in mitochondria....................35
Rexo2 plays an important role in ribonucleotide salvage in human mitochondria....................36
Role of Rexo2 in deoryribonucleotide salvage pathway....................37
Conclusion....................38
Tables....................39
Table 1. X-ray data collection and crystal structure refinement statistics for RNase R mutant ∆HTH-K.....................39
Table 2. X-ray data collection and crystal structure refinement statistics for Rexo2-RNA and Rexo2-DNA complexes.....................40
Figures....................41
References....................67

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