Research Projects

The study aims to investigate the molecular mechanism of the degradation of cytoplasmic DNA by TREX1, a nuclease involved in the process. The researchers suggest that cytosolic DNA containing alkyl adducts may be resistant to TREX1 degradation, leading to the accumulation of alkylated DNA in the cytosol. They will use high-resolution mass-spectrometry to examine the extent of endogenous alkylation in cytoplasmic DNA, and synthetic oligonucleotides containing specific DNA alkyl-adducts to identify which alkyl-adducts are particularly resistant to TREX1-mediated degradation. They will also use an in vitro assay to examine the effect of DNA containing abasic sites or methyl-adducts on CGAS activity. The study will also investigate whether cytoplasmic ALKBH3 can augment TREX1 activity by removing DNA alkyl-adducts from the 3' mis-paired end of cytosolic DNA. The project's outcome will help to understand the mechanisms behind the accumulation of alkylated DNA in metastatic cancer cells.