Background
Efficient synthesis of new protein is essential in sustaining tumour cell growth and proliferation. Therefore, drugs targeting the translation apparatus have demonstrated potent anti-tumor activity. Our group discovered a novel methyltransferase enzyme, called METTL13, that methylates two different residues of the eukaryotic elongation factor 1α (eEF1A), which is a key component of the cellular translation elongation machinery. We found that METTL13-mediated methylation of eEF1A is required for efficient protein synthesis (Jakobsson et al. Nature Comm., 2018). In addition, several studies have demonstrated an important role of METTL13 in promoting cancer growth, which suggests METTL13 is a promising therapeutical target. Furthermore, accumulating evidence has indicated that METTL13 has a great potential as a clinical biomarker for early diagnosis and prevention.
Goal
We aim to study METTL13 as a clinical target by i) identifying chemical compounds that specifically inhibit the METTL13 activity, as a strategy for targeting protein synthesis and cancer growth; and ii) evaluating its activity as a potential biomarker for diagnosis.
Project plan
By performing a high throughput screening, we have identified three potential METTL13 inhibitors and we are currently validating the effect of these drugs. It has been previously shown a synergistic effect in cancer growth when depleting METTL13 in combination with Omipalisib, an anti-cancer drug expected to interfere with the initiation step of translation. We have also generated METTL13 KO in four different cell lines and confirm the expected synergistic effect with Omipalisib. We then hypothesis that our potential METTL13 inhibitors should show a synergistic effect with Omipalisib.
The Master student will
i) evaluate the effect of these drugs in combination with Omipalisib by performing synergistic assays;
and ii) generate the required cell lines for performing rescue assays to reverse the synergistic effect observed either in genetically or pharmacologically METTL13 inhibited cells.
The second goal of our project aims to evaluate METTL13 as a biomarker in cancer. We are currently optimizing an ELISA assay that allows us to quantify METTL13 activity. The Master student will participate in quantifying and analyzing METTL13 activity in patient cancer samples by using specific antibodies that recognize the eEF1A methyl modification mediated by METTL13 (that we have developed) to assess whether such methylation may have potential as a biomarker.
What we offer the student
- Experience with cell culture techniques, transfection and drug treatment assays.
- Experience with synergistic and rescue assays
- Experience in molecular biology and biochemistry methods such as ELISA, protein enrichment, patient sample preparation, etc.
- Learn in the filed of protein methylation in cancer
- Training in transferrable skills: presentations, writing, project planning
- Be part of an international research team with researchers at different stages of their careers
- Frequent opportunities to get input on your data (weekly lab meetings) and to get updated on the most recent advances in our field of interest (“journal club” presentations)
- We have an ambitious environment where team members share their expertise to help each other to improve their career prospects and intellectual enrichment.
Our research group
The biological methylation research group is led by Prof P?l Falnes and consists of 5 members from different countries. The group is a young and dynamic environment and has long experience in supervision of Masters and PhD students. Our group is part of the Department for Bioscience (IBV) at UiO where we share facilities, reagents and expertise with other groups in both our department and around UiO