Mutations in the humanTREX1 gene contribute to disease in a spectrum of autoimmune disorders including systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and Aicardi-Goutieres syndrome (AGS). The dimeric TREX1 enzyme provides the major 3'->5'exonuclease activity in human cells, and failure to efficiently dispose of DNA and RNA polynucleotides from dying cells is a key driver of nucleic acid-mediated innate immune activation and autoinflammatory disease. How the disease causing mutations affect the biological function of TREX1, and how they affect the ability of TREX1 to process different DNA substrates are two open questions that are critical to our understanding of how TREX1 dysfunction leads to autoimmune disease. We propose that the dominant TREX1 mutations leading to disease are specifically defective in their ability to degrade double- stranded DNA during cell death, pointing to the likely cellular mechanism of immune activation. These studies will use a combination of structural and biochemical experiments to determine the structure of TREX1 in complex with double-stranded DNA (aim 1), uncover the biochemical mechanism of regulation by the dimeric structure of the protein (aim 2), and define the mechanism of catalytic regulation by protein ubiquitination (aim 3).
This research proposal is to study how the TREX1 enzyme functions to degrade double-stranded DNA. Multiple studies have associated mutations in the TREX1 gene with activation of innate immunity, lupus, and Aicardi-Goutieres syndrome (AGS). This research will address significant questions in an area of very high relevance for patients with autoimmune disease
|Mauney, Christopher H; Rogers, LeAnn C; Harris, Reuben S et al. (2017) The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch. Antioxid Redox Signal 27:1317-1331|
|Grieves, Jessica L; Fye, Jason M; Harvey, Scott et al. (2015) Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc Natl Acad Sci U S A 112:5117-22|
|Davis, Ryan R; Shaban, Nadine M; Perrino, Fred W et al. (2015) Crystal structure of RNA-DNA duplex provides insight into conformational changes induced by RNase H binding. Cell Cycle 14:668-73|