One of the hallmarks of the autoimmune disease Lupus is the development of an immune reaction that produces autoantibodies to one’s own DNA. Although the source of this DNA has not been firmly established, it is known that in adults about 100 billion cells undergo normal cell death processes each day.

As part of this normal process these dying cells must disassemble the 2.9 billion base pairs of DNA that comprise the human genome present in each and every cell.

Discovery of the TREX1 Gene

Work in the Perrino laboratory resulted in the discovery of the TREX1 gene that encodes a powerful DNA disassembly enzyme that appears to be responsible, in part, for this DNA removal process.

When the TREX1 enzyme does not function properly, the DNA from dying cells persists and an inappropriate immune response is initiated. The effects of this immune response vary in autoimmune patients, but the failure of TREX1 to eliminate DNA from dying cells might be at the root cause of the aberrant immune reaction in some Lupus patients.

Studies in the lab are focused on how TREX1 enzyme dysfunction leads to the development of Lupus and related autoimmune disorders.

Understanding the Causes of Human Autoimmune Diseases

The Perrino laboratory is collaborating to examine structure, mechanism, and function of the enzymes that cause a spectrum of human autoimmune diseases including Lupus, Aicardi-Goutieres Syndrome, Familial Chilblain Lupus, and Retinal Vasculopathy and Cerebral Leukodystrophy.

Our studies are directed at unraveling the mechanistic details of the TREX1 and RNase H2 enzymes to better understand the molecular actions of these DNA and RNA processing enzymes and the pathways through which mutations in these enzymes lead to autoimmune disease.

The human genome is susceptible to damage by many chemicals produced naturally in cells or by environmental exposure. The biological consequence of this damage is relevant to mutagenesis, to carcinogenesis, and to cancer therapeutics.

Despite our recognition of DNA damage as a path to mutagenesis our knowledge concerning the response of the human DNA polymerases and nucleases to the damage inflicted on DNA is limited. Additional studies in the laboratory on TREX2 and the lesion bypass DNA polymerases are directed at understanding how damaged DNA is processed to prevent mutation and cancer.