TY - JOUR
T1 - Cisplatin induces cytoplasmic to nuclear translocation of nucleotide excision repair factors among spiral ganglion neurons
AU - Guthrie, O'neil W.
AU - Li-Korotky, Ha Sheng
AU - Durrant, John D.
AU - Balaban, Carey
N1 - Funding Information:
The authors would like to thank Drs. Catherine Palmer and Sheila Pratt for helpful discussions and Chia-Yi Lo and Gloria Limetti for expert technical assistance. This work was supported by NIH-NIDCD (F31 DC05757-03), the K. Leroy Irvis Award and the SHRS Research Development Fund, all awarded to OWG and the Eye and Ear Institute Foundation (CDB).
PY - 2008/5
Y1 - 2008/5
N2 - Genomic DNA is a high-affinity target for the antineoplastic molecule cisplatin. Cell survival from cisplatin DNA damage is dependent on removal of cisplatin-DNA adducts by nucleotide excision repair (NER) pathways. The rate-limiting steps in the NER pathways are DNA damage identification and verification. These steps are accomplished by xeroderma pigmentosum complementation group C and A (XPC and XPA) and RNA polymerase II. Unlike RNA polymerase II, XPC and XPA have no known cellular function beyond DNA repair. Cisplatin is known to damage spiral ganglion neurons at the basal coil of the cochlea therefore it was posited that cisplatin may target their DNA and mobilize XPC and XPA. Female Fisher344 rats were given two, four day cycles of cisplatin (2 mg/kg) or saline, separated by a 10 day rest period. A 2 × 3 × 2 factorial design, consisting of two treatment conditions (cisplatin and saline treatment), three survival times (5, 19 and 22 days) and two analysis methods (quantitative RT-PCR and immunohistochemistry) was employed to evaluate the expression and distribution of XPC and XPA. Quantitative RT-PCR revealed statistically significant differences in cochlear XPC and XPA mRNA levels after cisplatin treatment at all times except day 22 for XPA. Immunohistochemistry revealed that a proportion (∼50%) of spiral ganglion neurons in control rats showed cytoplasmic expression of XPC and XPA. After cisplatin treatment, a similar proportion (∼50%) of spiral ganglion neurons showed increased nuclear expression of XPC and XPA, which appears to represent translocation from the cytoplasm. Basal coil spiral ganglion neurons translocated XPC and XPA at later treatment cycles and with less magnitude than apical coil neurons after cisplatin treatment. Therefore, it is suggested that cisplatin treatment induces nuclear translocation of NER proteins among spiral ganglion neurons and that this nuclear translocation is less efficient at the base relative to the apex.
AB - Genomic DNA is a high-affinity target for the antineoplastic molecule cisplatin. Cell survival from cisplatin DNA damage is dependent on removal of cisplatin-DNA adducts by nucleotide excision repair (NER) pathways. The rate-limiting steps in the NER pathways are DNA damage identification and verification. These steps are accomplished by xeroderma pigmentosum complementation group C and A (XPC and XPA) and RNA polymerase II. Unlike RNA polymerase II, XPC and XPA have no known cellular function beyond DNA repair. Cisplatin is known to damage spiral ganglion neurons at the basal coil of the cochlea therefore it was posited that cisplatin may target their DNA and mobilize XPC and XPA. Female Fisher344 rats were given two, four day cycles of cisplatin (2 mg/kg) or saline, separated by a 10 day rest period. A 2 × 3 × 2 factorial design, consisting of two treatment conditions (cisplatin and saline treatment), three survival times (5, 19 and 22 days) and two analysis methods (quantitative RT-PCR and immunohistochemistry) was employed to evaluate the expression and distribution of XPC and XPA. Quantitative RT-PCR revealed statistically significant differences in cochlear XPC and XPA mRNA levels after cisplatin treatment at all times except day 22 for XPA. Immunohistochemistry revealed that a proportion (∼50%) of spiral ganglion neurons in control rats showed cytoplasmic expression of XPC and XPA. After cisplatin treatment, a similar proportion (∼50%) of spiral ganglion neurons showed increased nuclear expression of XPC and XPA, which appears to represent translocation from the cytoplasm. Basal coil spiral ganglion neurons translocated XPC and XPA at later treatment cycles and with less magnitude than apical coil neurons after cisplatin treatment. Therefore, it is suggested that cisplatin treatment induces nuclear translocation of NER proteins among spiral ganglion neurons and that this nuclear translocation is less efficient at the base relative to the apex.
KW - Cisplatin
KW - DNA adduct
KW - Nucleotide excision repair
KW - Ototoxicity
KW - Spiral ganglion neurons
KW - Xeroderma pigmentosum
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U2 - 10.1016/j.heares.2008.01.013
DO - 10.1016/j.heares.2008.01.013
M3 - Article
C2 - 18329831
AN - SCOPUS:43049097827
SN - 0378-5955
VL - 239
SP - 79
EP - 91
JO - Hearing Research
JF - Hearing Research
IS - 1-2
ER -