TY - JOUR
T1 - Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q
AU - Marinovic-Terzic, Ivana
AU - Yoshioka-Yamashita, Atsuko
AU - Shimodaira, Hideki
AU - Avdievich, Elena
AU - Hunton, Irina C.
AU - Kolodner, Richard D.
AU - Edelmann, Winfried
AU - Wang, Jean Y.J.
PY - 2008/9/16
Y1 - 2008/9/16
N2 - 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.
AB - 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.
KW - Chemotherapy
KW - Cisplatin
KW - MLH1
KW - Mismatch repair
KW - p73
UR - http://www.scopus.com/inward/record.url?scp=52949143488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52949143488&partnerID=8YFLogxK
U2 - 10.1073/pnas.0806435105
DO - 10.1073/pnas.0806435105
M3 - Article
C2 - 18768816
AN - SCOPUS:52949143488
SN - 0027-8424
VL - 105
SP - 13993
EP - 13998
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -