Title: Molecular recognition in post-transcriptional regulation 2
Funder: Medical Research Council

Abstract: Multifunctional eukaryotic regulatory proteins and their viral functional equivalents control gene expression by interacting with mRNAs in large macromolecular aggregates. Dissection of the molecular basis of post-transcriptional regulatory mechanisms has a direct medical relevance, as changes in the regulation of mRNA metabolism lie at the basis of common genetic diseases, cancer and viral infection. Current therapies for these diseases do not focus on the post-transcriptional steps of regulation but rather on the transcriptional ones, that are better understood. Our aim is to clarify the structure-function relation that is at the basis of mRNA recognition by post-transcriptional regulatory proteins and to suggest strategies to control this recognition. Adenine-uracil-rich element (ARE)-mediated mRNA decay (AMD) regulates the concentration of mRNAs that contain AREs within their 3 untranslated regions (3 UTRs) by promoting their degradation. Transient AMD shut-off up-regulates the stability of these mRNAs and is important for processes that require a fast response of the organism such as cellular growth, immune response, cardiovascular toning and external stress-mediated pathways. However, impaired AMD and the consequent pathological long-term increase in the stability of a subset of mRNAs have been related to several types of cancer (skin tumours, colorectal cancer, Hodgkins lymphoma, lung carcinoma and leukaemia) and auto-inflammatory diseases (Crohn-like inflammatory bowel disease and inflammatory arthritis). K-homology splicing regulator protein (KSRP) is an important player in AMD that interacts with several different AREs mediating the degradation of the corresponding mRNAs. Our work centers on the analysis of the structural and functional elements that contribute to KSRP-RNA interactions and to mRNA degradation. We are studying the structure and dynamics of the different domains of the protein and investigated their relationship to mRNA degradation. Using structural and functional information, we plan to dissect the details of the interaction with the RNA and help the design of a strategy for the tuning of KSRP activity. Herpes viridae induced infections are a major threat to immunodepressed patients, increasing the risk of transplants and chemotherapy and reducing the life expectancy of AIDS sufferers. Current herpes virus therapies (e.g. Acyclovir) aim to block the synthesis of new DNA, but resistance to these treatments is increasing. Successful viral replication is achieved through the tightly regulated expression of viral genes. A key component of the regulatory mechanism is ICP27, an essential HSV-1 RNA binding protein that regulates protein expression, both at the transcriptional and post-transcriptional level. We will study both ICP27 and the mechanism of post-transcriptional regulation acted upon by this protein, in particular 3 mRNA editing. Using the same strategy described above for the protein KSRP, we will obtain a better understanding of the regulatory cycle of the virus and define specific structural features amenable to structure-aided drug design.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION