Our work seeks to understand nuclear function, with particular emphasis on splicing and transcription efficiency.
Our work centers upon understanding the functional organization of the nucleus. In particular, we are interested in understanding how certain human diseases alter nuclear efficiency. The nucleus contains a myriad of dynamic, highly organized domains, territories and bodies. All of these structures somehow work together; seamlessly allowing important nuclear activities, such as RNA synthesis and processing, to occur in an efficient manner. In certain disease states, the organization of the nucleus is altered. We hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect ribonucleoprotein (RNP) maturation, resulting in decreased pre-mRNA and rRNA processing. One nuclear structure altered by some diseases is the Cajal body (CB). Various diseases are correlated with the disruption of the CB or alteration in its protein composition. Two examples are Spinal Muscular Atrophy (SMA) and Machado-Joseph disease. In Machado-Joseph disease, CBs are tethered to large inclusions caused by an expanded polyglutamine tract mutation in the protein ataxin-3. In Spinal Muscular Atrophy (SMA), the composition of the CB is altered because an important protein, known as SMN, is no longer enriched in this structure. SMN is crucial for the cytoplasmic phase of small nuclear RNP (snRNP) biogenesis and localizes in the nucleus to the CB. It is possible that SMN chaperones newly imported snRNPs (which are needed for pre-mRNA splicing) to the CB where they are modified.
We hypothesize that the phosphorylation status of coilin impacts CB formation and snRNP biogenesis.
We are also conducting experiments designed to understand the normal cellular dialogue that occurs between some subnuclear domains. For example, it has been known for some time that Cajal bodies and another nuclear structure, known as the PML body, occasionally abut one another. We have found that CBs and PML bodies can simultaneously associate near U2 snRNA gene loci. It is possible that such an arrangement facilitates the transcription of this gene and experiments are underway to confirm this hypothesis. Additionally, since Cajal bodies are especially prevalent in cancer cells, identification and characterization of proteins that induce the formation of this structure may lead to novel cancer therapeutics.