We are recruiting for PhD studies starting in September 2019
The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC funded Doctoral Training partnership between the University of Birmingham, University of Warwick and the University of Leicester.
1. Transcriptional responses to cellular stress
The aim of the project is to understand how eukaryotic cells remodel RNA biology in order to survive stress generated by pathological conditions and external stressors.
2. Roles of transcriptional factors in RNA:DNA hybrids formation
The project aims to uncover novel roles for transcriptional factors and to investigate how mRNA 3’ end maturation alters gene expression in human cells.
The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC-funded doctoral training. The stipend is at Research Council UK (RCUK) standard rate plus additional travel allowance in the first year.
UK students, EU students
We are looking for a highly motivated, driven and enthusiastic person interested in RNA biology. Applicants should have a strong background in molecular biology and hold or expect to obtain a first class degree (or at least 2:1) or equivalent in genetics/molecular biology/medicine or relevant field.
Enquiries about the post should be directed to Dr Pawel Grzechnik (P.L.Grzechnik(at)bham.ac.uk).
Deadline: 6th January 2020
Project 1 : Transcriptional responses to cellular stress
Cellular stress has been implicated in aging and various diseases, including cancer, cardiac arrest, and neurological disorders. Exposure to acute stress like extreme temperatures, accumulation of reactive oxygen species or high salt concentration reduces cell viability or fitness and therefore immediate adaption is crucial for cell survival. Such rapid change of cell physiology requires coordinate and precise alternation of gene expression. One of the most dramatic transformations happens at the transcriptional level. Transcription of large number of genes is shut down while stress responders are activated and robustly transcribed. Synthesized stress-induced mRNA are not subjected to quality control and are exported to cytoplasm via specific, promoter-dependent mechanisms.
Such unusual mRNA biology of stress induced genes enables cells to immediately tailor protein production and allows them to survive extreme conditions.
In eukaryotic cells mRNA 3' end processing, which involves endonucleolytic cleavage followed by the addition of the poly(A) tail, is one of the most important steps in gene expression regulation.
For example, the 3’ end maturation complex responds to cellular stimuli and decides about the nuclear and cytoplasmic fate of mRNA through the generation of distinct 3’ end termini. Furthermore, a poly(A) tail protects mRNA from degradation and promotes translation. The function of the cleavage and polyadenylation machinery extends far beyond simple maturation of mRNA ends.
Recent studies reveal that cellular stress such as osmotic shock, viral infections or carcinogenesis can all affect mRNA 3’ end formation. Thus, the goal of this project is to employ a wide range of high-throughput and classic RNA analysis to investigate how the mRNA 3’ processing regulates expression of stress-induced genes and contributes to the cellular stress response in a model organism Saccharomyces cerevisiae and human cells.
Project 2 : Roles of transcriptional factors in RNA:DNA hybrids formation
The 3’ end processing of mRNA, which involves cleavage of the nascent transcript and synthesis of the poly(A) tail, is essential for mRNA stability, export and translation. Recent studies demonstrate that permanent changes in mRNA processing mimics the result of mutations in DNA and can also severely affect cell metabolism and lead to pathological conditions.
A successful candidate will study functions of human protein CREPT (Cell cycle-Related and expression-Elevated Protein in Tumor) which is overexpressed in ~80% of tumors. CREPT interacts with RNA Polymerase II and is present on actively transcribed genes. Consistently, CREPT was shown to regulate expression of cell-cycle related genes. CREPT depletion also results in accumulation of RNA:DNA hybrids (R loops) and increased DNA damage. R loops are deleterious three-strand nucleic acid structures formed by hybridization of the nascent RNA with the DNA template. R loops form in various locations in the genome including genes 3’ regions containing transcription termination and 3’ end processing signals. However, excessive R-loops accumulation leads to mutations of the displaced DNA strand and as a result to genomic instability.
Therefore, the aim of this project is to investigate roles for CREPT in mRNA synthesis with a special focus on R-loop formation. The outcome of this research will help to better understand regulation of gene expression in eukaryotic cells.