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

Abstract

The cellular response to DNA damage signaling by mismatch-repair (MMR) proteins is incompletely understood. It is generally accepted that MMR-dependent apoptosis pathway in response to DNA damage detection is independent of MMR’s DNA repair function. In this study, we investigate correlated motions in response to the binding of mismatched and platinum cross-linked DNA fragments by MutSα, as derived from 50 ns molecular dynamics simulations. The protein dynamics in response to the mismatched and damaged DNA recognition suggests that MutSα signals their recognition through independent pathways providing evidence for the molecular origin of the MMR-dependent apoptosis. MSH2 subunit is indicated to play a key role in signaling both mismatched and damaged DNA recognition; localized and collective motions within the protein allow identifying sites on the MSH2 surface possible involved in recruiting proteins responsible for downstream events. Unlike in the mismatch complex, predicted key communication sites specific for the damage recognition are on the list of known cancer-causing mutations or deletions. This confirms MSH2’s role in signaling DNA damage-induced apoptosis and suggests that defects in MMR alone is sufficient to trigger tumorigenesis, supporting the experimental evidence that MMR-damage response function could protect from the early occurrence of tumors. Identifying these particular communication sites may have implications for the treatment of cancers that are not defective for MMR, but are unable to function optimally for MMR-dependent responses following DNA damage such as the case of resistance to cisplatin.

An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:15

Keywords:

• correlated motions
• collective motions
• signal transduction by MSH2
• MMR-dependent apoptosis
• DNA-damage signaling
• MMR repair function

Acknowledgments

This research was partially supported by NIH R01CA129373 to FRS. The computations herein were performed on the WFU DEAC cluster; we thank WFU’s Provost’s office and Information Systems Department for their generous support.

Notes

aIn italic are residues associated with mismatched complex, or proposed for the repair signaling. Unmarked are residues found involved in correlations unique for the PCL complex, or proposed for apoptosis signaling. Underlined are the common residues. Certain residues on the list were found as correlated pairs. The proposed residues were predicted as correlated with residues on the list, found to be involved in multiple correlations (the case of K353 and N538 from MSH2, as well as 715–718, 695, 696, 698–706, 793–795 and 797 from MSH6), or the case of highly significant correlations in the repair system that became weak.