Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

To gain insights into frameshifting, mutants of translation components have been sought that cause altered levels of programmed frameshifting, act as suppressors of frameshift mutants or else were later found to influence them (440, 587) . A systematic study of this for Ty1 has just been completed (213) and only a few will be briefly mentioned here. Roles emerged for proteins such as Asc1/RACK1 (588) , and the mammalian and bacterial ribosomal proteins L4 and L9, respectively (484, 589) . There is an intriguing connection between L9, whose N-terminal domain binds to the L1 stalk and which stretches via a long alpha helical region 80 around the outside so that its Cterminal RNA binding domain can be near S6 on the small subunit (590) (Figure 17) , and the bacterial counterpart, EF-P, of hypusine containing eEF5 (591) . [The C-terminal domain of L9 restrains forward mRNA slippage (484) (Figure 17 ) and L9 is required for the growth of EF-P deficient cells (591) .] Such studies also pointed to the care needed to avoid indirect effects, though they can be insightful for other processes. Searches for mutants of S. cerevisiae that increase frameshifting on an MMTV shift cassette sequence, and independently of L-A virus frameshifting (with loss of a satellite virus that encodes a killer toxin), led to the isolation of mutants of the UPF1 and UPF2 genes (592, 593) . Follow up work led to controversy that was only resolved with the demonstration that UPF mutants do not affect frameshift- ing, though they do affect product levels (594, 595) . [UPF genes are key mediators of NMD (nonsense mediated decay) and their name is derived from 'up-frameshift mutant suppressor' to reflect one of the paths taken to their discovery (596) .]