Regulation of CD4 T cell and HIV-1 gene expression by Sam68

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Humans have ~20,000 genes and over 50 trillion cells. However, the C. elegans worm has ~20,000 genes and ~1000 cells. Therefore, human complexity is not determined by the number of genes. Instead, human genes are highly regulated in terms of how many different proteins can be made from a single gene using processes such as alternative splicing and alternative polyadenylation. Also, genes are controlled in terms of when they are expressed by being transcribed into RNA and how efficiently this RNA is translated into protein. There is still little understanding of how RNA binding proteins control how many different proteins and how much of a specific protein is made from a gene. This proposal will determine how the cellular RNA binding protein Sam68 controls RNA abundance from specific genes, how efficiently this RNA is translated into protein, and how many different proteins can be made from that gene. We will analyse this in human CD4 T cells, which are an essential component of the immune system that protects the body from infections. We will determine how the location of Sam68 binding sites on an RNA controls its ability to regulate which proteins are expressed from a gene through alternative splicing. We will also analyse whether the genes that Sam68 regulates control important functions for the immune system. Sam68 is implicated in several types of cancer including breast, prostate, colorectal, cervical and renal cell carcinoma as well as the diseases fragile X-associated tremor/ataxia syndrome (FXTAS) and spinal muscular atrophy (SMA). Understanding how Sam68 controls gene expression may also help us understand how Sam68 regulates these diseases.HIV infection causes AIDS and is a worldwide pandemic. Currently, there are approved antiviral drugs targeting four steps of the HIV life cycle. However, drug resistant strains of HIV are a problem and there is still a great need for new drug targets. One promising approach to develop novel antiviral drugs is to target cellular proteins. HIV has only nine genes and must highjack hundreds of cellular proteins to replicate. Sam68 regulates HIV gene expression but it is unclear how it does so. It is also unknown if HIV infection alters which cellular proteins are expressed by interacting with Sam68, especially if the cell and virus have to compete for it. Therefore, we will determine how HIV interacts with Sam68 to control cellular and viral gene expression. This may determine if Sam68 or other steps of HIV gene expression are potential drug targets.