Response to the Formal Letter of Z. Chrzanowska-Lightowlers and R. N. Lightowlers Regarding Our Article “Ribosome Rescue and Translation Termination at Non-Standard Stop Codons by ICT1 in Mammalian Mitochondria”

Most deviations from the universal genetic code exist in the mitochondrial translation system. In human mitochondria, two arginine codons, AGA and AGG, have no cognate tRNAs; mtDNA-encoded cytochrome c oxidase subunit I (MTCO1) and NADH dehydrogenase 6 (MTND6) carry AGA and AGG codons at the end of their mRNAs, respectively. We previously demonstrated in vitro the possible engagement of ICT1 in the translation termination at nonstandard stop codons ofMTCOI andMTND6mRNAs. On the other hand, Temperley and colleagues proposed in 2010 that human mitoribosomes invoke a -1 frameshift at the terminal AGA/AGG codons placing standard UAG stop codon in the ribosomal A-site. As consequence, only a single release factor, mtRF1a/RF1Lmt, would be used in mitochondria. Here we revisit the frameshift model and explain the view that ICT1 is presently a plausible candidate for the termination factor for non-standard stop codon in human mitochondria.