Genome stability versus transcript diversity

Abstract

Our genome is protected from the introduction of mutations by high fidelity replication and an extensive network of DNA damage response and repair mechanisms. However, the expression of our genome, via RNA and protein synthesis, allows for more diversity in translating genetic information. In addition, the splicing process has become less stringent over evolutionary time allowing for a substantial increase in the diversity of transcripts generated. The result is a diverse transcriptome and proteome that harbor selective advantages over a more tightly regulated system. Here, we describe mechanisms in place that both safeguard the genome and promote translational diversity, with emphasis on post-transcriptional RNA processing.

Keywords: DNA damage response; DNA repair; Polymerase fidelity; Post-transcriptional RNA processing; Protein translation; Proteomic diversity; RNA splicing; RNA transcription.

Figure 1. Decoding the genome leads to diversity

(a) At each step along the transfer of genetic information, errors are produced. In all domains of life, replication and repair of DNA are overall rigid, high-fidelity systems for safeguarding the genome. Transcribing and decoding this information, however, is more error-prone, leading to diverse transcriptomes and proteomes. Represented here is the flow and magnitude of errors (as black arrows) along a route from DNA to RNA to proteins. Some processes are outlets (brown text), whereby malformed products are removed, such as with apoptosis (removal of cells), RNA degradation (removal by the RNA exosome), and protein degradation (removal by the ubiquitin proteasome system). Perturbations, such as cell stress, can increase error rates of many processes (indicated by red circles). Each step has an associated error rate, which may have been measured experimentally, and indicated in green where available. Green question marks represent areas where error rates (or rates or error disposal) have not been conclusively obtained. (b) For all organisms, erroneous protein translation plays a significant role in generating evolutionary diversity beyond what is contained in the genome. However, in multicellular eukaryotes, complex transcriptional and posttranscriptional mechanisms (alternative transcription initiation, splicing, stability, etc.) have greatly expanded the potential proteome. Here, the realized accumulation of diversity is represented by a widening arrow from genome to gene product. The bubbles on the sides represent expanding diversity due to process errors and contraction due to quality control measures (see points indicated by “errors” and “QC”). Contraction is akin to outlets as described in (a).