My research focuses on gene expression in the human mitochondrion. The organelle has its own genome and the transcribed RNA is translated in organello. My work aims to identify and understand the molecular mechanisms underlying these processes. We are currently identifying and isolating factors that are important for modulating post-transcriptional regulation in the human mitochondrion. Main questions we are addressing include: What are the trans- and cis-acting elements that can determine mitochondrial mRNA stability ? What proteins are required to mediate translation termination ? How are the mitoribosomes recycled ?
Co-Leader of the RNA Biology Group with Dr J Brown
RNA Interest Group Co-ordinator
Chair Curriculum Committee (MRes)
BSc (Hons) Biological Sciences, University of East Anglia
PGCE, University of London
MSc, University of Oregon
PhD, University of Newcastle
The mitochondrion is an organelle found in all nucleated cells of higher eukaryotes. It is the site of oxidative phosphorylation and contains its own genome that encodes 13 proteins, which are essential components of these respiratory complexes. In addition to the mRNAs the genome also encodes the 22tRNAs and 2 rRNAs that are required for this intra-mitochondrial protein synthesis.
It is the fate of these mitochondrial mRNA species that we are investigating. Although much is known about the turnover of cytosolic and bacterial transcripts, until very recently almost nothing was clear about the mitochondrial RNA species. Do they behave as their bacterial ancestors or follow the example of the cytosol in which they reside ? What is the normal decay mechanism and what are the enzymes responsible for carrying out these activities ? We have identified that in contrast to yeast, the mammalian mt-transcripts are polyadenylated but the function of this tail is not yet certain. In bacteria it enhances decay, whilst in the eukaryote cytosol it is bound by poly(A) binding proteins and promotes both stability and translation.
Since the mitochondrial genome cannot yet be manipulated we have used cell lines with identified mutations to try and answer some of these questions. Most of the mt-mRNAs require polyadenylation to generate the Stop codon. By using a cell line that has a 2 base pair microdeletion the resulting mRNA loses the termination codon we have identified a ‘non-stop’ decay mechanism and shown that in this situation the poly(A) tail confers stability to the aberrant transcript.
Our work is presently focussed on identifying the mitochondrial nucleases and mt-RNA-binding proteins involved in the mechanism described above as well as those involved in the normal deadenylation and decay and characterising their specificity. We are also looking at the release factors and recycling factors that are likely to be responsible for terminating translation.
Within our department the link between pure and clinical research is very strong. Many of the neurological conditions that patients present with affect their mitochondrial DNA. In some instances this would be predicted to affect the subsequent transcription and translation. This provides the opportunity to study the differences in the homeostasis of mitochondrial mRNA in controls versus disease.
I currently supervise 5 postgraduate PhD students and am tutor to MRes students.
The Wellcome Trust and the EU currently support the ongoing research in my laboratory
RNA metabolism, mitochondrial RNA, degradation, mitochondrial gene expression, polyadenylation, stability
I have hosted final Honours year undergraduates in my lab for their research project work for over 10 years.
I am the Deputy Director for the suite of MRes courses in Medical and Molecular Biosciences.
I am also the Chair of the Curriculum Committee and Director for Admissions and Recruitment.
I am programme director for the MRes in Mitochondrial Biology and Medicine.
I host Erasmus students from numerous European countries as well as MRes project students in my group.
I am responsible for a number of home, EU and International PhD students that I supervise.
I am also on the Management Committee for Training for the BRC/BRU programme.
I am involved in the assessment and marking of MBBS, BSc and MRes student courses.