A Search for Biologically Relevant Examples of the DNA Self-Depurination Mechanism

Abstract

Self-catalyzed depurination (SDP) has been associated with increased mutagenic potential in vitro and in vivo. A recent investigation of the self-depurinating sequence within the β-globin gene provides compelling evidence that self-catalyzed depurination is biologically relevant. In this thesis, I present a search effort for additional examples of the biological relevance of the self-depurination (SDP) mechanism. I first analyzed the genomes of T4 and related bacteriophages and found no significant examples of functional SDP sites. An extension of these initial efforts led to the discovery of SDP sites playing a role in the evolutionary history of 7SL-derived RNAs. It appears that evolutionary pressure created an SDP site in a functionally important region and that the pressure for this site to self-erase led to mutations that affect the transcription and functionality of the encoded active RNAs. Additionally, the evolutionary success of the Alu SINE and the BC200 RNA is in part due to these SDP-induced mutations. I also present a discussion of self-depurination in mobile DNA. Taken together, these findings provide additional support for the biological relevance of the SDP mechanism.