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Structural and mechanistic studies of RNA-ligating deoxyribozymes
von Almudena Ponce-SalvatierraIn structural terms, the differences between functional RNA and DNA molecules are rather dramatic. RNA adopts complicated folds within various ribozymes and riboswitches. For example, some ribozymes, like group II introns or the ribosomal RNA, are organized by means of tertiary interactions to an overwhelming level of complexity, only comparable to the one of proteins.
Despite the fact that DNA and RNA are virtually identical in terms of building blocks, DNA generally adopts much simpler conformations. The majority of known DNA structures lack long-range tertiary interactions. One reason for the conformational simplicity of DNA appeared to be the absence of the 2‘-OH group, resulting in greater chemical stability of DNA and rendering it suitable for its role as a long-term storage molecule of genetic information.
In contrast, the catalytic properties of synthetic DNA catalysts (deoxyribozymes) were expected to depend on the ability of these molecules to fold into compact teritary structures, as in the case of ribozymes or protein enzymes. However, until this work was reported, no structure of any deoxyribozyme was known, thus leaving the question “how does DNA fold in order to perform catalysis?” largely unanswered.
The scope of this thesis was to understand how DNA molecules fold in 3D to achieve enzymatic properties, therefore I decided to investigate a DNA catalyst able to ligate two RNA molecules. Here I report the structure of this DNA-based RNA ligase in complex with its RNA product.
Despite the fact that DNA and RNA are virtually identical in terms of building blocks, DNA generally adopts much simpler conformations. The majority of known DNA structures lack long-range tertiary interactions. One reason for the conformational simplicity of DNA appeared to be the absence of the 2‘-OH group, resulting in greater chemical stability of DNA and rendering it suitable for its role as a long-term storage molecule of genetic information.
In contrast, the catalytic properties of synthetic DNA catalysts (deoxyribozymes) were expected to depend on the ability of these molecules to fold into compact teritary structures, as in the case of ribozymes or protein enzymes. However, until this work was reported, no structure of any deoxyribozyme was known, thus leaving the question “how does DNA fold in order to perform catalysis?” largely unanswered.
The scope of this thesis was to understand how DNA molecules fold in 3D to achieve enzymatic properties, therefore I decided to investigate a DNA catalyst able to ligate two RNA molecules. Here I report the structure of this DNA-based RNA ligase in complex with its RNA product.