# Leishmania donovani elongator protein Elp3a plays a crucial role in modulating the parasite response to genotoxic stress

## TL;DR

This study explores how the Elp3a protein in Leishmania donovani helps the parasite survive genotoxic stress, finding it non-essential for normal growth but important under DNA-damaging conditions.

## Contribution

The study reveals a novel role of Elp3a in modulating genotoxic stress response in Leishmania donovani, despite the protein being non-essential for basic survival.

## Key findings

- Elp3a is not essential for the survival of Leishmania donovani under normal growth conditions.
- Elp3a-depleted parasites show increased tolerance to certain genotoxic agents like methyl methane sulfonate and hydroxyurea.
- The protective effect of Elp3a is not due to enhanced DNA damage response but reduced DNA damage itself.

## Abstract

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 Leishmania donovani. The elp3a 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 per se. 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 elp3 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 Leishmania species, perhaps in synchrony with the fact that the Elp1–6 holocomplex itself does not seem to be present in these parasites.

Leishmaniases 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 Leishmania donovani 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.