Coding, or non-coding, that is the question

Coding, or non-coding, that is the question

2024 | Laura Poliseno, Martina Lanza and Pier Paolo Pandolfi
The advent of high-throughput sequencing revealed that the human genome is pervasively transcribed into RNAs, many of which are not translated into proteins. Non-coding RNAs (ncRNAs) outnumber protein-coding genes, challenging the traditional definition of "gene." Recent studies show that some ncRNAs can be translated into peptides, blurring the coding/non-coding distinction. This review discusses examples where genes produce both coding and non-coding products, highlighting the implications for gene expression and biological outcomes. It also addresses methodological challenges in studying these genes and their potential in anticancer therapies. Non-coding RNAs, including housekeeping ncRNAs (rRNAs, tRNAs, snRNAs, snoRNAs) and regulatory ncRNAs (miRNAs, lncRNAs, circRNAs, NATs, pseudogenes), play crucial roles in gene regulation, development, and disease. miRNAs, for example, regulate gene expression by binding to target mRNAs, while lncRNAs and circRNAs can act as sponges for miRNAs or regulate transcription and splicing. Pseudogenes, though often considered non-functional, can also be translated into peptides and have roles in cancer. Genomic loci can express both mRNA and ncRNA, with examples including alternative splicing, back-splicing, and antisense transcripts. These loci, termed "bifunctional," can have conflicting or complementary functions. For instance, the SRA1 gene expresses both an oncogenic protein and a lincRNA, while the PPP1R10 gene produces a nuclear targeting subunit and a lncRNA. Similarly, the Zbtb7a gene generates both a tumor suppressor and an oncogenic circRNA. mRNAs can also exert non-coding functions through their 5'UTR, CDS, and 3'UTR. The 5'UTR of c-MYC can act as a tumor suppressor, while the 5'UTR of VEGF can promote oncogenesis. The CDS of p53 can interact with MDM2, influencing its activity. The 3'UTR of mRNAs can act as ceRNAs, sponging miRNAs and affecting gene expression. Non-coding RNAs can also be translated into peptides, such as miPEPs from pri-miRNAs and ncPEPs from lincRNAs and pseudogenes. These peptides can have oncogenic or tumor-suppressive roles, as seen in CIP2A-BP and SMIM30. This review underscores the complexity of gene expression and the importance of considering both coding and non-coding functions in understanding and developing anticancer therapies.The advent of high-throughput sequencing revealed that the human genome is pervasively transcribed into RNAs, many of which are not translated into proteins. Non-coding RNAs (ncRNAs) outnumber protein-coding genes, challenging the traditional definition of "gene." Recent studies show that some ncRNAs can be translated into peptides, blurring the coding/non-coding distinction. This review discusses examples where genes produce both coding and non-coding products, highlighting the implications for gene expression and biological outcomes. It also addresses methodological challenges in studying these genes and their potential in anticancer therapies. Non-coding RNAs, including housekeeping ncRNAs (rRNAs, tRNAs, snRNAs, snoRNAs) and regulatory ncRNAs (miRNAs, lncRNAs, circRNAs, NATs, pseudogenes), play crucial roles in gene regulation, development, and disease. miRNAs, for example, regulate gene expression by binding to target mRNAs, while lncRNAs and circRNAs can act as sponges for miRNAs or regulate transcription and splicing. Pseudogenes, though often considered non-functional, can also be translated into peptides and have roles in cancer. Genomic loci can express both mRNA and ncRNA, with examples including alternative splicing, back-splicing, and antisense transcripts. These loci, termed "bifunctional," can have conflicting or complementary functions. For instance, the SRA1 gene expresses both an oncogenic protein and a lincRNA, while the PPP1R10 gene produces a nuclear targeting subunit and a lncRNA. Similarly, the Zbtb7a gene generates both a tumor suppressor and an oncogenic circRNA. mRNAs can also exert non-coding functions through their 5'UTR, CDS, and 3'UTR. The 5'UTR of c-MYC can act as a tumor suppressor, while the 5'UTR of VEGF can promote oncogenesis. The CDS of p53 can interact with MDM2, influencing its activity. The 3'UTR of mRNAs can act as ceRNAs, sponging miRNAs and affecting gene expression. Non-coding RNAs can also be translated into peptides, such as miPEPs from pri-miRNAs and ncPEPs from lincRNAs and pseudogenes. These peptides can have oncogenic or tumor-suppressive roles, as seen in CIP2A-BP and SMIM30. This review underscores the complexity of gene expression and the importance of considering both coding and non-coding functions in understanding and developing anticancer therapies.
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