Mismatch repair proteins in recurrent prostate cancer.

Normal cell function requires strict control over the repair of DNA damage, which prevents excessive mutagenesis. An enhanced accumulation of mutations results in the multistep process generally known as carcinogenesis. Defects in repair pathways fuel such mutagenesis by allowing reiterative cycles of mutation, selection, and clonal expansion that drive cancer progression.

Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment.

We, and others, have previously shown that mismatch repair proteins, in addition to their repair function, contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins.

Cooperative nuclear localization sequences lend a novel role to the N-terminal region of MSH6.

Human mismatch repair proteins MSH2-MSH6 play an essential role in maintaining genetic stability and preventing disease. While protein functions have been extensively studied, the substantial amino-terminal region (NTR*) of MSH6 that is unique to eukaryotic proteins, has mostly evaded functional characterization. We demonstrate that a cluster of three nuclear localization signals (NLS) in the NTR direct nuclear import.

Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response.

Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a "death conformation" of the MutS homologous proteins that is distinguishable from their "repair conformation." This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death.

Mismatch repair protein deficiency compromises cisplatin-induced apoptotic signaling.

Mismatch repair (MMR) proteins participate in cytotoxicity induced by certain DNA damage-inducing agents, including cisplatin (cis-diamminedichloroplatinum(II), CDDP), a cancer chemotherapeutic drug utilized clinically to treat a variety of malignancies. MMR proteins have been demonstrated to bind to CDDP-DNA adducts and initiate MMR protein-dependent cell death in cells treated with CDDP; however, the molecular events underlying this death remain unclear. As MMR proteins have been suggested to be important in clinical responses to CDDP, a clear understanding of MMR protein-dependent, CDDP-induced cell death is critical.

The elevated expression of a mismatch repair protein is a predictor for biochemical recurrence after radical prostatectomy.

Purpose: The inability to predict clinical outcome of prostate cancer is a major impediment to effective treatment decisions and patient counseling. New markers of recurrence are needed to improve the accuracy of risk assessment and treatment of prostate cancer. Our previous studies identified a mismatch repair protein, PMS2, to be elevated in prostate cancer; here, we investigate the prognostic potential of this marker.

Small molecule induction of MSH2-dependent cell death suggests a vital role of mismatch repair proteins in cell death.

Avoidance of apoptosis is one of the hallmarks of cancer development and progression. Chemotherapeutic agents aim to initiate an apoptotic response, but often fail due to dysregulation. MSH proteins are capable of recognizing cisplatin damage in DNA and participate in the initiation of cell death.

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6.

The major eukaryotic mismatch repair (MMR) pathway requires Msh2-Msh6, which, like Escherichia coli MutS, binds to and participates in repair of the two most common replication errors, single base-base and single base insertion-deletion mismatches. For both types of mismatches, the side chain of E. coli Glu38 in a conserved Phe-X-Glu motif interacts with a mismatched base.

Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer.

Background: Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis.

The molecular mechanism of DNA damage recognition by MutS homologs and its consequences for cell death response.

We determined the molecular mechanism of cell death response by MutS homologs in distinction to the repair event. Key protein-DNA contacts differ in the interaction of MutS homologs with cisplatinated versus mismatched DNA. Mutational analyses of protein-DNA contacts, which were predicted by molecular dynamics (MD) simulations, were performed.