Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q

Ivana Marinovic-Terzic, Atsuko Yoshioka-Yamashita, Hideki Shimodaira, Elena Avdievich, Irina C. Hunton, Richard D. Kolodner, Winfried Edelmann, Jean Y.J. Wang

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13993-13998
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number37
DOIs
StatePublished - Sep 16 2008

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Keywords

  • Chemotherapy
  • Cisplatin
  • MLH1
  • Mismatch repair
  • p73

ASJC Scopus subject areas

  • General

Cite this

Marinovic-Terzic, I., Yoshioka-Yamashita, A., Shimodaira, H., Avdievich, E., Hunton, I. C., Kolodner, R. D., Edelmann, W., & Wang, J. Y. J. (2008). Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q. Proceedings of the National Academy of Sciences of the United States of America, 105(37), 13993-13998. https://doi.org/10.1073/pnas.0806435105