Genome-wide transcriptome and translatome analyses reveal the role of protein extension and domestication in liver cancer oncogenesis

Abstract

One gene could be transcribed to different RNA isoforms, and then produce various forms of protein sequences. This mechanism largely diversifies the cellular pool and allows natural selection to select from a wider range of substrates. In the cancer field, the isoform switches between tumor and normal tissues, such as the alternative splicing, stop codon read-through, or protein domestication, are significantly ignored by the traditional differential expression analyses. The intention of this work is to fill this gap. We collected public transcriptome and translatome data from ten patients with liver cancer, and performed genome-wide comparison on the stop codon read-through and protein domestication events. Both events diversify the proteome during long-term evolution. Surprisingly, we found that the tumor tissues globally have higher occurrence of stop codon read-through events as well as protein domestication events (translation signals of non-coding repetitive elements). These read-through and domestication events show limited overlapping across the ten patients, indicating the randomness of their occurrence and their deleterious nature. These tumor-specific events might have been purged by natural selection if they are not collected timely. Our work manifests the role of protein extension and domestication in liver cancer oncogenesis, adding new aspects to the cancer field.

Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection

“…Importantly, VEGF-Ax possesses anti-angiogenic activity opposite that of VEGF-A, and its expression is depleted in colon adenocarcinoma, suggesting that this translational readthrough event is manipulated by cancer cells to their advantage. Consistent with this notion, genomic-wide studies have revealed higher levels of stop codon readthrough in cancer cells (Wang and Wang, 2021). Although the detailed biochemical mechanism of stop codon readthrough remains to be deciphered, the fact that alteration of RQC activity can result in stop codon readthrough (Annibaldis et al, 2020), and that loss of a recently identified RQC factor EDF1 in yeast can result in frame-shifting at stall sites (Wang et al, 2018), suggests the potential involvement of RQC factors in this process.…”

C-terminal sequence stability profiling in Saccharomyces cerevisiae reveals protective protein quality control pathways

“…Thus, correctly formed proteins are in general stable, whereas extended proteins are destabilized by triggering PQC, which protects the cell from potentially deleterious effects of non-natural proteins. The importance of the latter mechanism is underscored by increased translational read-through events that are detectable in tumor tissues ( 83 ).…”

Comparative genomic analysis of a naturally born serpentized pig reveals putative mutations related to limb and bone development

“…During long-term evolution, highly deleterious mutations have been eliminated and could no longer be seen at present time [ 25 ]. Beneficial mutations increase their frequency in natural populations [ 26 ] but the net gain of fitness is so subtle to be observed at phenotypical level [ 27 ]. This dilemma adds difficulty to the functional verification of mutations and makes the evolutionary theories hard to guide experimental biologists [ 28 ].…”