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 (; Msh2 subunit is colored in lavender, Msh6 subunit is colored in salmon) in complex with (DNA is shown in cyan with the mismatch pair marked: crimson for thymine and white for guanine) and cisplatin-induced platinum-DNA adduct 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.
MutSα consists of : the mismatch binding domain (residues 1–124 in MSH2 and 1–157 in MSH6, in red); the connector domain (residues 125–297 in MSH2 and 158–356 in MSH6, in yellow); the lever domain (residues 300–456 and 554–619 in MSH2 and 357–573 and 648–714 in MSH6, in green); the clamp domain (residues 457–553 in MSH2 and 574–647 in MSH6, in darkmagenta); the ATPase domain (residues 620–855 in MSH2 and 715–974 in MSH6, in blue). The MSH2 subunit is indicated to play a key role in signaling both mismatched and damaged DNA recognition and many of these (shown in spacefill representation), 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.
