RNA based regulation of Gene Expression - Peter Lukavsky
CEITEC MU CEITEC MU
RNA based regulation of Gene Expression - Peter Lukavsky

PhD Topics

1. Integrative structural biology of 3’UTRs

Supervisor: Peter Lukavsky, Dr. rer. nat.

Consultants: Boris Tichý, Ph.D., assoc. prof. Zbyněk Zdráhal

Annotation: The non-coding part of the genome vastly increased from worm to humans while the number of protein-coding genes remained constant. This expansion includes 3’UTRs of mRNAs with an average length of 1.2 kb in humans and functions in mRNA transport, translational control and mRNA decay. Despite the importance of 3’UTRs for spatial and temporal control of gene expression, the molecular basis of 3’UTR functions is largely unknown. We will determine complexes of 3’UTR signals with Staufen1 protein and the ribosome which regulate mRNA stability and control translation. Using integrative structural biology approaches, including NMR spectroscopy and cryo-EM, we will unravel the molecular basis of Staufen-mediated 3’UTR functions in posttranscriptional regulation of gene expression and thus provide new insights into how deregulation can lead to diseases such as cancer and neurodegeneration.  We are looking for highly motivated PhD candidates with background in biochemistry and biophysics who share our fascination for RNA-protein interactions regulating gene expression.

Literature:

  1. Sugimoto et al, Nature 2015, 519:491-4.
  2. Yadav & Lukavsky, Prog. Nucl. Magn. Reson. Spectrosc. 2016, 97:57-81.
  3. Gleghorn & Maquat, . 2014, 39:328-40.

Keywords: Three Prime Untranslated Region, 3’UTR, mRNPs, RNA-protein networks, Staufen, RNA-based pulldown, gene expression, 3’UTR mutations, cryo EM, NMR spectroscopy

 

2. RNA as a drug target

Supervisor: Peter Lukavsky, Dr. rer. nat.

Annotation: Most small molecule therapeutics target proteins and out of the 20,000 human protein coding genes about 2000-3000 are considered disease-related but current drugs only target less than 700 proteins leaving most of the genome untouched.  On the other hand, more than 70% of the genome is translated into non-protein-coding RNAs and mRNAs also contain large non-coding portions, so-called 5’ and 3’ UTRs which contain many regulatory elements for spatio-temporal regulation of gene expression, such as translational control, RNA transport and localization and mRNA decay.  We propose to target non-coding mRNA elements with small molecules to alter gene expression.  We will focus on cancer and neurodegenerative diseases, where protein targets often lack druggable elements and therefore targeting them on the mRNA level is an attractive alternative.  Our research aims to identify functional mRNA motifs that can bind small molecules and to reveal common small molecule scaffolds which interact with similar 3D RNA structures and thus form a basis for rational lead optimization.

We are looking for highly motivated PhD candidates with background in biochemistry and biophysics who share our fascination for RNAs regulating gene expression.

Literature:

  1. Nagel et al, EMBO Reports, 2016, 17, 1516.
  2. Di Giorgio et al, Med. Chem. Commun., 2019, 10, 1424.

Keywords: targeting non-coding mRNA, gene expression, neurodegenerative diseases, cancer, mRNA motifs, cryo EM, NMR spectroscopy