To account for the substantial differences in sequence and domain organization, it has been suggested to group 5 0 -3 0 RNA ligases in bacteriophages, yeast, plants, and animals into classes [66, 87] ; however, no uniform nomenclature has become generally accepted to date. Biochemical studies revealed that ligation of tRNA exon halves in vertebrates and archaea is mainly achieved by an alternative mechanism. A 3 0 -5 0 RNA ligase activity resulting in incorporation of the precursor-derived 2 0 ,3 0cyclic phosphate into the splice junction as a 3 0 ,5 0 -phosphodiester was for the first time detected in HeLa cell extracts (Fig. 2B, central box) [53, 56, 97] . The same reaction has later been shown to occur in archaeal cell extracts [54, 98, 99] . Intensive attempts to identify the human tRNA ligase proteins by chromatographic purification were triggered by these initial findings [100, 101] . Recently, chromatographic purification led to the identification of RtcB/HSPC117 proteins as 3 0 -5 0 RNA ligases in the crenarchaeon Pyrobaculum aerophilum and in humans [102, 103] . Concurrently, a candidate approach revealed RtcB in Escherichia coli as a 3 0 -5 0 RNA ligase [104] . The high degree of conservation of HSPC117/RtcB proteins suggested a shared role for this protein family in many organisms already during their initial characterization [102] [103] [104] .