Lene Songe-Møller successfully defends PhD thesis on Alkbh8-mediated formation of wobble uridine modifications (2011)

tRNA molecules usually contain several different post-transcriptional modifications, and such modifications are essential for tRNA function. Located at specific sites throughout the tRNA body they facilitate correct folding and contribute to stabilizing the tertiary structure. Moreover, modified residues in the anticodon of tRNAs are important to ensure efficient and accurate decoding during translation, as well as to maintain a correct reading frame. 

In this thesis we have studied the function of the E. coli AlkB homolog ALKBH8 in mammals. Through studies of three mice models and the recombinant human ALKBH8/TRM112 methyltransferase complex, we have demonstrated that ALKBH8 performs the final methylation step during formation of the tRNA wobble uridine modification mcm⁵U in mammals. This methylation step is required for the subsequent 2-thiolation and ribose methylation leading to mcm⁵s²U and mcm⁵Um, respectively. In addition we also report that the AlkB domain of Alkbh8 hydroxylates mcm⁵U into (S)-mchm⁵U in tRNA^Gly. Furthermore, we demonstrate that oxidative stress induced by the genotoxic agent methyl methanesulfonate (MMS) has a tremendous effect on the expression of the selenoprotein Gpx1 in Alkbh8^-\- cells. Gpx1 protein disappears following oxidative stress, whereas the level of other selenoproteins such as Txnrd1 and SelN are not substantially altered. 

Mismodifications of tRNA might lead to aggregation of non-functional proteins, which is typical for several neurological diseases. It is therefore possible that ALKBH8 plays an important role in maintaining an optimal nervous system and preventing neurological diseases.