Understanding how weak protein-protein interactions modulate DNA mismatch repair
Dr. Alba Guarne (McMaster University)
Abstract: DNA mismatch repair (MMR) is a conserved pathway that safeguards genome integrity by correcting replication errors. The coordinated actions of two proteins (MutS and MutL) initiate the mismatch repair response and defects in the genes encoding these proteins have been linked to sporadic and hereditary cancers. The processivity clamp, typically known to tether the replicative polymerase to DNA during DNA synthesis, also has key roles in several steps of MMR including initiation, mismatch excision, and strand re-synthesis. We have shown that MutL interacts with both MutS and the processivity clamp. Both interactions are essential for mismatch repair activity in vivo, but they are short-lived and, therefore, have been difficult to study at a molecular level. In this talk, I will discuss the approaches that we have used to stabilize these transient protein complexes. Altogether, our work unveils how recognition of a mismatch by MutS leads to nicking of the newly synthesized strand by MutL and provides new avenues to stabilize transient protein-protein interactions for structural characterization.
Bio: My research program is aimed at understanding the molecular mechanisms that coordinate DNA replication and repair. In particular, the protein-protein and protein-DNA interactions that orchestrate the DNA damage response using biochemical, biophysical and structural biology techniques. Since most of these interactions are short-lived, we are also interested on developing methods to stabilize transient/weak interactions and bringing new technology to McMaster to study these types of systems. On this front, we have acquired the first Rigaku BioSAXS (biological small-angle X-ray scattering) home system in Canada and have established McMaster as a reference site for SAXS experiments of biological samples.