Research Interest |
Structural Insights into DNA and RNA Metabolism
We study DNA- and RNA-binding proteins that are involved in nucleic
acid metabolism. The overall goal is to discover the structure-based
mechanism of these proteins in DNA/RNA recognition, processing and
degradation. We use X-ray crystallography, together with other
biophysical and biochemical approaches, to reveal the molecular
mechanism and the structure-to-function relationships of these
proteins. We have studied the function and determined the crystal
structures of apoptotic DNases that degrade chromosomal DNA during
apoptosis. We also work on various RNases that process RNA precursors
in RNA maturation, or degrade miRNA and mRNA for translation regulation
and RNA turnover. Over-expression, mutations or misfolding of most of
the proteins we study are linked to human diseases, ranging from
neurodegenerative disorders to autoimmune diseases. Therefore,
understanding how these proteins participate in DNA and RNA metabolism
and how they lose their functions may not only advance our knowledge of
nucleic acids metabolism, but also pave the way for future development
of disease treatment strategies. Our major projects are briefly
described below. DNA degradation by apoptotic DNases
DNA degradation in apoptosis is the basic and essential process for
animal development and tissue homeostasis. Failure to degrade DNA of
apoptotic cells can induce immune responses and lead to autoimmune
diseases. We analyze the biochemical properties and crystal structures
of these apoptotic nucleases and component proteins to show how they
work for cooperative DNA degradation. We also study how these proteins
process DNA/RNA in non-apoptotic cells. RNA processing and decay
RNA decay plays a key role in gene expression regulation and RNA
quality control. Messenger RNA decay is performed by various enzymes,
including endoribonucleases, exoribonucleases and helicases. We
characterize the structure and function of these RNA-processing
enzymes, including the bacterial RNA degradosome and mitochondrial
exosome, to elucidate how RNA is degraded at a molecular level. Aggregation-prone RNA-binding proteins
RNA-binding proteins play the primary roles in RNA metabolism. Aberrant
expression or functioning of RNA-binding proteins is thus frequently
associated with human diseases, including neurologic disorders. We
study aggregation-prone RNA-binding proteins, including TDP-43, to
determine how they are folded for RNA binding and how they are
misfolded and aggregated in diseased neuronal cells. |