Ribosomal frameshifting at normal codon repeats recodes functional chimeric proteins in human.

Ribosomal frameshifting refers to the process that ribosomes slip into +1 or -1 reading frame, thus produce chimeric trans-frame proteins. In viruses and bacteria, programmed ribosomal frameshifting can produce essential trans-frame proteins for viral replication or regulation of other biological processes. In humans, however, functional trans-frame protein derived from ribosomal frameshifting is scarcely documented. Combining multiple assays, we show that short codon repeats could act as cis-acting elements that stimulate ribosomal frameshifting in humans, abbreviated as CRFS hereafter. Using proteomic analyses, we identified many putative CRFS events from 32 normal human tissues supported by trans-frame peptides positioned at codon repeats. Finally, we show a CRFS-derived trans-frame protein (HDAC1-FS) functions by antagonizing the activities of HDAC1, thus affecting cell migration and apoptosis. These data suggest a novel type of translational recoding associated with codon repeats, which may expand the coding capacity of mRNA and diversify the regulation in human.

Effects of dietary restriction on genome stability are sex and feeding regimen dependent.

Preserving genome stability is essential to prevent aging and cancer. Dietary restriction (DR) is the most reproducible non-pharmacological way to improve health and extend lifespan in various species. Whether DR helps to preserve genome stability and whether this effect is altered by experimental variables remain unclear. Moreover, DR research relies heavily on experimental animals, making the development of reliable in vitro mimetics of great interest. Therefore, we tested the effects of sex and feeding regimen (time-restricted eating, alternate day fasting and calorie restriction) on genome stability in CF-1 mice and whether these effects can be recapitulated by cell culture paradigms. Here, we show that calorie restriction significantly decreases the spontaneous micronuclei (MN), a biomarker of genome instability, in bone marrow cells of females instead of males. Alternate day fasting significantly decreases cisplatin-induced MN in females instead of males. Unexpectedly, daily time-restricted eating significantly exacerbates cisplatin-induced MN in males but not in females. Additionally, we design several culture paradigms that are able to faithfully recapitulate the key effects of these DR regimens on genome stability. In particular, 30% reduction of serum, a mimetic of calorie restriction, exhibits a strong ability to decrease spontaneous and cisplatin-induced MN in immortalized human umbilical vein endothelial cells. We conclude that the effects of different DR regimens on genome stability are not universal and females from each diet regimen sustain a more stable genome than males. Our results provide novel insight into the understanding of how DR influences genome stability in a sex and regimen dependent way, and suggest that our in vitro DR mimetics could be adopted to study the underlying molecular mechanisms.