The Model for RNA-Based, Frame-Shift Peptide Production in Tumor Cells (IMAGE)
Caption
Errors in DNA replication are very rare and repaired. Transcription error rates are higher but also rare as are mis-splicing during intron excision. Additionally, the FS transcript with a premature termination may be degraded by Nonsense Mediated Decay (NMD). Aberrant proteins, including those with frameshifts are largely eliminated by the protein quality control system, Ubiquitin/Proteasome System (UPS). The net result is that very few frameshift peptides are presented on MHC I/II or escape the cell to be presented to the immune system. Cancer Cell: All levels of information transfer become more error prone. More errors are made in DNA replication, but only when cells divide. Most DNA mutations are point mutations and encode low or non-immunogenic epitopes. Global transcription is increased and is generally less accurate and even more so through MSs producing INDELs. Most transcribed genes with MSs in the coding region will have more FS transcripts. RNA splicing is also far less accurate, creating more FS transcripts from each out-of-frame splicing between exons from the same gene and different genes. The substantial increase of the FS transcripts from INDEls of MS and mis-splicing overwhelms the RNA quality control systems, such as NMD. Consequently, more truncated proteins with the FS peptide will be translated. These unfolded truncated proteins, combined with aberrant proteins from other mutations, overwhelms the protein quality control system, leading to more frameshift peptides being presented on MHC I/ II and mis-secreted or released from the cancer cell which the immune system can respond to.
Credit
Arizona State University
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