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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

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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 4

NAD+-mediated enhancement of NER efficiency requires SIRT2 and is independent of SIRT1.

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NAD+-mediated enhancement of NER efficiency requires SIRT2 and is indepe...
(A) Western blot showing the activation effects of 5 nM NAD+ on SIRT2 expression and deacetylase activity (n = 3), which is indicated by the level of α-tubulin AcK40. (B) NAD+ administration enhanced NER efficiencies in a SIRT2-dependent manner in neuronally differentiated 50B11 cells (n = 3). (C) Western blot showing the effects of administration of 5 nM NAD+ on SIRT1 expression and deacetylase activity in 50B11 cells in which SIRT1 expression is modified using siRNA against SIRT1 (n = 3). Deacetylase activity is indicated by acetylation of p53 at K373/K382 (AcK373.382). (D) SIRT1 expression and activity did not affect NAD+-mediated enhancement of NER efficiencies in 50B11 cells (n = 3). Statistical significance was assessed using 2-way ANOVA with Bonferroni’s correction (B and D). *P < 0.05; **P < 0.01; ***P < 0.001.

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