A Role for the Mutagenic DNA Self-Catalyzed Depurination Mechanism in the Evolution of 7SL-Derived RNAs.

ABSTRACT

The Alu element, the most prevalent SINE (short interspersed element) in the human genome, is one of the many RNA-encoding genes that evolved from the 7SL RNA gene. During analysis of the evolution of 7SL-derived RNAs, two distinct evolutionary intermediates capable of self-catalyzed DNA depurination (SDP) were identified. These SDP sequences spontaneously create apurinic sites that can result in increased mutagenesis due to their error-prone repair. This DNA self-depurination mechanism has been shown both in vitro and in vivo to lead to substitution and short frameshift mutations at a frequency that far exceeds their occurrence due to random errors in DNA replication. In both evolutionary intermediates, the same self-depurination sequence overlaps motifs necessary for successful transcription and SRP9/14 (signal recognition particle) binding; hence, mutations in this region could disrupt RNA activity. Yet, the 7SL-derived RNAs that arose from the elements capable of SDP show significant diversity in this region, and every new sequence retains the transcription and SRP9/14-binding motifs, even as it has lost the SDP sequence. While some (but not all) of the mutagenesis can be alternatively attributed to CpG decay, the very fact that the self-depurinating sequences are selectively discarded in all cases suggests that this was evolutionarily motivated to prevent further destructive mutagenesis by the SDP mechanism.