Non-specific Nucleases in Cell Defense

A variety of non-specific nucleases are involved in cell defense by degradation of foreign or host nucleic acid molecules in prokaryotes and eukaryotes. We are interested in understanding and comparing the ways of how these nucleases are regulated, how they recognize DNA/RNA, and how they cleave phosphodiester linkages, using a combination of structural, biochemical and biophysical approaches.

We have been working on two types of sugar non-specific nucleases in bacteria, including a periplasmic nuclease Vvn and a secreted toxin ColE7, both of which digest foreign nucleic acids for cell defense. Based on our structural and biochemical analysis on Vvn and ColE7, we have provided a solid foundation to explain how these nucleases are inhibited and activated, how they recognize DNA without sequence specificity and how they digest DNA to protect bacterial cells at atomic level.

We also extend our investigation to the eukaryotic non-specific nucleases involved in cell defense. Specific projects include structural and functional studies of non-specific nucleases participating in chromosome fragmentation in apoptosis, and a number of RNases involved in mRNA degradation and miRNA biogenesis. For example, we determined the crystal structure of a cell-death-related nuclease (CRN4), suggesting how this protein binds and cleaves DNA in program cell death. Our structural and biochemical analysis on human Tudor-SN suggests how this protein captures hyper-edited miRNA and plays a role in RNA editing and interference. The long-term goal of this research is to establish molecular bases for how nucleases digest DNA/RNA to assert their roles in promoting or suppressing cell survival machinery.