Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic SignalingS

• Published in: The Journal of biological chemistry Vol. 284; no. 21; pp. 14029 - 14039
• Main Authors: Topping, Ryan P., Wilkinson, John C., Scarpinato, Karin Drotschmann
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 22-05-2009
• Subjects: DNA: , Repair, Recombination, and Chromosome Dynamics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M809303200

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.
In this report, we demonstrate MMR protein-dependent relocalization of
cytochrome
c
to the cytoplasm and cleavage of caspase-9, caspase-3,
and poly(ADP-ribose) polymerase upon treatment of cells with CDDP. Chemical
inhibition of caspases specifically attenuates CDDP/MMR protein-dependent
cytotoxicity, suggesting that a caspase-dependent signaling mechanism is
required for the execution of this cell death. p53 protein levels were
up-regulated independently of MMR protein status, suggesting that p53 is not a
mediator of MMR-dependent, CDDP-induced death. This work is the first
indication of a required signaling mechanism in CDDP-induced, MMR
protein-dependent cytotoxicity, which can be uncoupled from other CDDP
response pathways, and defines a critical contribution of MMR proteins to the
control of cell death.