Abstract
Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcription factors with proapoptotic activity. The human PMS2 is highly polymorphic, with at least 12 known nonsynonymous codon changes identified. We show here that the PMS2(R20Q) variant is defective in activating p73-dependent apoptotic response to cisplatin. When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin. Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin measured by clonogenic survival. Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic allele may modulate tumor responses to cisplatin among cancer patients.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism
-
Adenosine Triphosphatases / deficiency
-
Adenosine Triphosphatases / genetics*
-
Adenosine Triphosphatases / metabolism*
-
Animals
-
Apoptosis* / drug effects
-
Arginine / genetics
-
Arginine / metabolism
-
Cell Line
-
Chlorocebus aethiops
-
Cisplatin / pharmacology
-
DNA Damage / genetics
-
DNA Repair Enzymes / deficiency
-
DNA Repair Enzymes / genetics*
-
DNA Repair Enzymes / metabolism*
-
DNA-Binding Proteins / deficiency
-
DNA-Binding Proteins / genetics*
-
DNA-Binding Proteins / metabolism*
-
Gene Expression Regulation
-
Glutamine / genetics
-
Glutamine / metabolism
-
Humans
-
Mice
-
Mice, Knockout
-
Mismatch Repair Endonuclease PMS2
-
MutL Protein Homolog 1
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Polymorphism, Single Nucleotide / genetics*
-
Protein Binding
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
DNA-Binding Proteins
-
MLH1 protein, human
-
Nuclear Proteins
-
Tumor Suppressor Proteins
-
Glutamine
-
Arginine
-
Adenosine Triphosphatases
-
PMS2 protein, human
-
Pms2 protein, mouse
-
Mismatch Repair Endonuclease PMS2
-
MutL Protein Homolog 1
-
DNA Repair Enzymes
-
Cisplatin