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

Content Provider	PubMed Central
Author	Ivana, Marinovic-terzic Yoshioka-yamashita, Atsuko Hideki, Shimodaira Elena, Avdievich Hunton, Irina C. Kolodner, Richard D. Edelmann, Winfried Wang, Jean Y. J.
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.
Related Links	http://dx.doi.org/10.1073/pnas.0806435105
Ending Page	13998
Page Count	6
Starting Page	13993
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	37
Volume Number	105
Language	English
Publisher	National Academy of Sciences
Publisher Date	2008-09-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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