<i>Leishmania donovani</i> elongator protein Elp3a plays a crucial role in modulating the parasite response to genotoxic stress

The eukaryotic elongator complex comprises six proteins Elp1-Elp6, with Elp3 being the catalytic subunit. In trypanosomatids, only Elp3 has been identifiable, and interestingly, these organisms have two Elp3 orthologs: Elp3a and Elp3b. This study was undertaken to examine the role of Elp3a in the trypanosomatid <i>Leishmania donovani</i>. The <i>elp3a</i> gene was successfully eliminated, with the insect form as well as mammalian form of the parasite surviving and propagating normally in its absence, signifying its non-essential nature under usual growth conditions. In examining the response of LdElp3a-depleted parasites to genotoxic agents, we found no behavioral differences in response to UV and camptothecin, but the parasites exhibited higher tolerance to methyl methane sulfonate and chronic hydroxyurea treatment. This was not due to a hyperactive DNA damage response in Elp3a-depleted cells; rather, these cells suffered less DNA damage <i>per se</i>. In looking for possible mechanisms by which Elp3a-depleted parasites were being protected from the effects of these genotoxic agents, we considered previous findings in yeast where Elp3 (as part of the Elp1-6 complex) had been found to play a role in the modification of transfer RNA uridines at the wobble position of anticodons, thus promoting translation efficiency. However, while yeast <i>elp3</i> mutants displayed a downregulation in translation of proteins carrying adenine residues at the wobble position of their codons, our experimental results suggest that this mechanism of regulation does not exist in <i>Leishmania</i> species, perhaps in synchrony with the fact that the Elp1-6 holocomplex itself does not seem to be present in these parasites.IMPORTANCELeishmaniases are a group of diseases endemic to 90 countries, putting over a billion people at risk of infection. No vaccines are available against this digenetic parasite that cycles between the insect host sandfly and the mammalian host. While drugs are available to treat the disease, their high costs and toxic side effects combined with the problems of emerging drug resistance continue to give a thrust to research in the areas of their cellular biology. The Elp3 protein in eukaryotes is known to modulate a myriad of processes. This study aims to investigate the role of the <i>Leishmania donovani</i> Elp3a protein. We find the protein is not essential for parasite survival but plays a role in moderating the parasite response to certain genotoxic stresses. Thus, Elp3a regulates one or more processes that help the parasite survive in inhospitable environments that trigger DNA damage.