The de Moor Lab
Dr Cornelia de Moor, Ms Asma Khurshid, Ms Hannah Parker
The research in my laboratory focuses on post-transcriptional gene regulation of mRNA and protein expression, especially by sequences downstream of the stop codon of the protein coding region. This type of gene regulation is much more common than previously thought, and includes modulation of mRNA stability, translational control, mRNA localisation and changes in nuclear polyadenylation. The regulation is generally mediated by RNA binding proteins, microRNAs and/or alternative polyadenylation. We study these processes in cell lines during cell adhesion and proliferation, during the inflammatory response and in human embryonic stem cells. Our work work has potential applications in the treatment of inflammatory diseases, cancer and regenerative medicine.
Cornelia de Moor says “I am very excited about our recent advances in the understanding of post-transcriptional control of gene expression, we are now combining our fundamental work on how genes control the production of proteins with possible applications in the treatment of disease such as asthma and cancer.”
We have a special interest in regulation mediated by the poly(A) tail of the mRNA, by polyadenylation or deadenylation. After transcription, mRNAs acquire a discreet poly(A) tail of around 200 residues in the nucleus, which aides their export to the cytoplasm and stimulates translation through formation of the so-called closed loop complex. This complex connects the factors binding at the cap of the mRNA with the proteins binding to the poly(A) tail (poly(A) binding proteins or PABPs) and helps recruit the ribosome, which mediates translation of the coding region of the mRNA into protein. The poly(A) tails of an mRNA is removed by deadenylase enzymes. The rate at which this happens is thought to determine how long an mRNA lives, due to efficient degradation once an mRNA reaches a minimum poly(A) tail length. In special cases, deadenylated mRNAs can regain a poly(A) tail through a process called cytoplasmic polyadenylation.
These commonly accepted rules implicate that mRNAs with a long poly(A) tail should be more abundant and better translated than mRNAs with a short or no poly(A) tail. However, we have discovered using a novel poly(A) fractionation method that some mRNAs accumulate with no or a very short poly(A) tail in mammalian cells (1), indicating that these rules are flawed and that more research is needed to define the role of the poly(A) tail in mRNA stability and translation.
These commonly accepted rules implicate that mRNAs with a long poly(A) tail should be more abundant and better translated than mRNAs with a short or no poly(A) tail. However, we have discovered using a novel poly(A) fractionation method that some mRNAs accumulate with no or a very short poly(A) tail in mammalian cells (1), indicating that these rules are flawed and that more research is needed to define the role of the poly(A) tail in mRNA stability and translation.
We also have been studying the polyadenylation inhibitor cordycepin. This compound is isolated from Cordyceps militaris, a rare species of mushroom that parasitizes caterpillars. Cordyceps fungi are famed in Chinese traditional medicine for their many beneficial properties. We have studied the effects of cordycepin on cell proliferation and found that the effect is mediated through a signal transduction pathway called the mTOR pathway, which ultimately reduces protein synthesis and affects cell adhesion (2). We are now investigating if these effects are through the inhibition of polyadenylation mediated by cordycepin, or through another mechanism. A collaboration with Sue Watson and Anna Grabowska in Pre-Clinical Oncology (University of Nottingham) on this subject is ongoing.
We have recently shown that cordycepin efficiently inhibits the inflammatory response. These effects are definitely mediated by the inhibition of polyadenylation, because knockdown of a poly(A) polymerase also reduces the inflammatory response. These data indicate that polyadenylation inhibitors are potential anti-inflammatory drugs and will be published soon. This work resulted from a fruitful collaboration with Linhua Pang and Alan Knox in the Division of Respiratory Medicine, which is continuing.
We have a long standing interest in microRNA mediated regulation MicroRNAs bind to mRNAs and either cause translational repression or destabilise the mRNAs, in both cases deadenylation occurs. We have collaborations on this subject with Tyson Sharp (University of Nottingham) and Martin Bushell (MRC Toxicology Unit, Leicester). Two publications have so far resulted (3,4).
In collaboration with Mark Searle and Jonas Emsley (both University of Nottingham), we are studying structure/function relationships in the CELF1 protein, a deadenylation factor involved in mRNA stability. A publication will appear soon.
A new project will start soon on the role of mRNA stability in the maintenance and induction of pluripotent stem cells. This is a collaboration with Lorraine Young of the Wolfson Centre for Stem Cell Research (University of Nottingham).
We have expertise in a number of specialised techniques related to poly(A) tail measurement, determination of mRNA stability and mRNA translation and are willing to train others in these techniques.
For publications on these subjects please click here.
Dr Cornelia de Moor (Lecturer in RNA Biology)
Ms Asma Khurshid (Postgraduate Student)
Ms Hannah Parker (Postgraduate Student)