Ribonucleic Acid (RNA) along with deoxyribonucleic acid (DNA) and protein composes the major material that is essential for all known forms of life. Life message written by more than 3 billion nucleotides in specific sequences that stored in cell nuclear needs variant RNA molecules to carry the information from nuclear to cytosol by messenger RNA (mRNA) and assemble a machinery to convert the sequence messages to proteins by tRNA and rRNA. In an typical human cell, there is about 10-50pg RNAs, 1.5 to 5 folds more that DNA contents, that mainly distribute in the cytoplasm. Some other types of RNAs, such as translation inhibiting small RNAs, eg. microRNAs and siRNAs, also play crucial roles in the regulations of gene activities. Aberrant RNA metabolism or abnormal function will most certainly lead to malfunction of the cells and therefore link to pathologic conditions.
RNA is also encoded by DNA in the nuclear. Most RNAs exert their function in the cytoplasm therefore the Nascent RNA synthesized in nuclear need to be transported to cytoplasm. Sophisticated processes take place on the RNA molecules during RNA maturation from nascent RNA, include 5’ capping, splicing and 3’ tailing, as well as RNA editing. Our laboratory has been work on the function and molecular mechanisms of RNA process, particularly the RNA editing process. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that binds to and changes the sequence information of RNA molecules. We have demonstrated that ADAR1 is an essential enzyme for animal survival and embryonic development. In ADAR1 knockout mice, the embryo die around day 11-12. Employing conditional and inducible knockout models, we also found that adult cells including adult stem cells require ADAR1 for their differentiation and normal functions. ADAR1 is dispensable for the organ homeostasis include liver, pancreas, intestine, T and B lymphocyte, skin. For example, in the liver specific knockout animal model, deletion of ADAR1 caused profound hepatocyte death and persistent liver regeneration that lead to severe liver function damage.
There are evidences that ADAR1 involves in interferon (IFN) signaling pathways. In ADAR1 knockout animals IFN levels and its regulated genes are upregulated. IFNs play critical roles in pathogen infections and also in inflammation responses. It conceivable that cells change their RNA content biologically or by pathogen invading that need ADAR1 to copy with. Inappropriate process of the RNAs will activate the IFN path cascade that could lead to severe tissue damage. We currently focus our interests in the function of ADAR1 in surgical pathological context. Hopefully our study will contribute to the better understanding of molecular mechanism of inflammation development in the surgical infection and trauma conditions.
NW607 UPMC Montefiore
Publications from the Wang Lab can be viewed through PubMed.