Journal:JBSD:15

The molecular origin of the MMR-dependent apoptosis pathway from dynamics analysis of MutSα-DNA complexes

Lacramioara Negureanu, Freddie R. Salsbury ^[1]

Molecular Tour
DNA mismatch repair proteins (MMR) maintain genetic stability, defects in which can cause a predisposition to cancer, and detect and initiate cellular response to certain types of DNA damage, making them a useful target for anticancer agents. Platinum-based anticancer agents, such as cisplatin, are commonly used anticancer agents that damage DNA and result in cell death. The pathway(s) from platinum-induced DNA damage to cell death are not fully understood. Experimental studies have shown that the cell-death response and DNA repair activity of MMR proteins are separable functions and previous computational work suggest that there are conformational differences between binding mismatched DNA and damaged DNA due to cisplatin. In this study, computational analysis of the dynamical response of the MMR recognition complex, MutSα (the proteins Msh2/Msh6 in human) in complex with mismatched DNA and cisplatin-induced platinum-DNA adduct (Figure 1) suggests that MMR proteins signals the mismatched and damaged DNA recognition through independent pathways, providing further evidence for the molecular origin of the MMR-dependent apoptosis. The MSH2 subunit is indicated to play a key role in signaling both mismatched and damaged DNA recognition and many of these residues are known to be in cancer-associated mutations (Figure 2), which is consistent with experimental studies that show that MMR-damage response function could protect from the early occurrence of tumors. We suggest that novel drug discovery approach in discovering and designing inhibitors that interact with the predicted mismatch signaling regions on the surface of Msh2 (Figure 3), as to severe these communications, but to promote the damage signaling, could be explored.