Can messenger ribonucleic acid (mRNA) be mutated?

Can mRNA Be Mutated?

Yes, messenger RNA (mRNA) can be mutated through various mechanisms, including both natural processes and engineered modifications that alter its nucleotide sequence or chemical structure. 1

Types of mRNA Mutations and Modifications

Natural Mutations

• mRNA can undergo mutations through transcriptional mutagenesis, where RNA polymerase incorrectly incorporates nucleotides during transcription, especially when encountering damaged DNA templates 2
• These transcriptional mutations can produce altered mRNA sequences that may result in the synthesis of mutant proteins 2
• Oxidative stress and other genotoxic insults can damage DNA and consequently drive transcriptional mutagenesis in both normal and cancer cells 2

Chemical Modifications (Epitranscriptome)

• The epitranscriptome consists of over 170 distinct chemical modifications that can occur on mRNA molecules, altering their structure, stability, localization, and translation efficiency 3, 4
• These modifications are deposited, removed, and recognized by specific enzymes known as writers, erasers, and readers, respectively 3
• Common mRNA modifications include methylation of adenosine (m6A), cytosine (m5C), and other nucleotides that can significantly affect mRNA function 4

Fragmentation and Processing

• mRNA can exist in both full-length and fragmented forms, with fragments ranging from 25 to 4000 nucleotides compared to typical cellular mRNAs of 400-12,000 nucleotides 1
• Fragmented mRNAs can produce proteins with different functions from their parental source 1

Mechanisms Affecting mRNA Mutations

Genetic Factors

• Mutations in cis-regulatory elements of DNA can affect mRNA synthesis, processing, and translation, leading to altered mRNA products 5
• These include mutations in enhancer or promoter regions, polyadenylation sequences, splice sites, and the Kozak sequence involved in translation initiation 5

Nonsense-Mediated Decay (NMD)

• Premature termination codons (PTCs) in mRNA can trigger nonsense-mediated mRNA decay, a quality control mechanism that degrades aberrant mRNAs 6
• The engagement of NMD depends on specific rules and can determine whether a mutated mRNA produces a truncated protein or is degraded 6

Engineered Modifications

• Prime editing technology allows for precise modification of mRNA through engineered prime editing guide RNAs (epegRNAs) that can introduce specific mutations 1
• This technique uses a Cas9 nickase and reverse transcriptase to copy a desired edit from the guide RNA into the target DNA, which is then transcribed into modified mRNA 1

Clinical Implications of mRNA Mutations

Disease Associations

• Alterations in mRNA modifications have been observed in a broad range of human diseases, including cancer, neurological disorders, and metabolic conditions 3, 4
• In colorectal cancer, specific microRNAs can regulate mRNA expression and stability, with dysregulation contributing to tumorigenesis 1
• Fragile X syndrome involves abnormal regulation of FMRP, an RNA-binding protein that regulates mRNA translation, particularly in neuronal dendrites 1

Therapeutic Considerations

• Understanding mRNA mutations and modifications is essential for developing targeted therapies 3
• In cancer immunotherapy, only frameshifted transcripts that escape nonsense-mediated decay predict a response to treatment 6
• mRNA vaccines, such as those for SARS-CoV-2, rely on the stability and proper processing of the introduced mRNA to generate an immune response 1

Research and Diagnostic Applications

• Analysis of mRNA modifications can serve as diagnostic biomarkers, particularly in cancer and other diseases 1
• High-throughput sequencing techniques allow for the detection and characterization of mRNA mutations and modifications 1
• Extracellular vesicles containing mRNA fragments show different profiles in healthy versus diseased states, offering potential for liquid biopsy applications 1

Understanding the complex landscape of mRNA mutations and modifications provides insights into disease mechanisms and opens avenues for novel diagnostic and therapeutic approaches targeting the epitranscriptome 3.