SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair
Manchao Zhang, … , Shengkai Jin, Fen Xia
Manchao Zhang, … , Shengkai Jin, Fen Xia
Published March 5, 2020
Citation Information: J Clin Invest. 2020;130(6):2953-2965. https://doi.org/10.1172/JCI123159.
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Research Article Neuroscience Oncology

SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair

Abstract

Platinum-based chemotherapy–induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA cross-links. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2’s protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2’s function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation–mediated neuroprotection during platinum-based cancer treatment.

Authors

Manchao Zhang, Wuying Du, Scarlett Acklin, Shengkai Jin, Fen Xia

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Figure 3

SIRT2 regulates TC-NER–mediated DNA cross-link repair.

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SIRT2 regulates TC-NER–mediated DNA cross-link repair. TC-NER efficiency...
TC-NER efficiency was analyzed using a TC-NER reporter assay. Luciferase expression and activity from a cisplatin-induced cross-linked CMV–firefly luciferase plasmid was calculated as a percentage of the expression/activity from a CMV–firefly luciferase control plasmid. (A) XPA-mutated cells were defective in NER-mediated repair of the cross-linked luciferase plasmid compared with XPA-complemented (C-XPA) cells (n = 5). (B) NER-mediated repair of cross-links was diminished in Sirt2-KO neuronally differentiated 50B11 and PC12 cells. Reexpression of WT-SIRT2, but not the enzymatically inactive mutant, HY-SIRT2, in KO cells restored NER efficiency (n = 3). Western blots (left inset) show rat SIRT2 (rSIRT2) and human SIRT2 (hSIRT2) expression in these cells. Vinculin was the protein loading control. (C) Dot blot for level of DNA-platinum adduct measurement in neuronally differentiated 50B11 cells following cisplatin or saline administration (n = 3). (D) Quantification of DNA dot blot (n = 2). Sirt2 KO resulted in an increase in DNA-platinum adduct formation following cisplatin treatment. Reexpression of WT-SIRT2 restored DNA-platinum adduct repair. Statistical significance was assessed using 2-tailed Student’s t test with Welch’s correction (A), 1-way ANOVA with Dunnett’s correction (B), or 2-way ANOVA with Bonferroni’s correction (D). **P < 0.01; ***P < 0.001.