The consequences of irradiation- and/or Cisplatin (IR/CisP)-induced neuronal toxicity, i.e., neurological function deficits, often irreversible and permanent, represent a daunting challenge when treating patients with cancer. The underlying mechanisms of toxicity remain poorly understood and the ability to selectively protect neuronal survival while not compromising tumor control following IR/CisP is lacking. This proposal aims to determine the mechanisms protecting neurons from IR/CisP-induced cytotoxicity, with the overarching goal to provide evidence supporting novel strategies to decrease their neurotoxicity, while maintaining therapy efficacy and improving patient quality of life. NAD+-dependent deacetylase sirtuin 2 (SIRT2), which is highly expressed in differentiated neurons, is involved in diverse cellular processes including metabolism, response to oxidative stress, and tumor suppression. Our preliminary study has discovered a novel signaling network that connects SIRT2 to transcription coupled- homologous recombination repair (TC-HRR) and -nucleotide excision repair (TC-NER) of DNA damage and neuronal cell resistance to IR/CisP-induced cytotoxicity. Furthermore, our data revealed that CSB, the key mediator for TC-HR/TC-NER, is directly deacetylated by SIRT2. Moreover, the cyclin-dependent kinase 5 (CDK5), which is involved in DNA damage signaling in neuron cells, phosphorylates and inhibits SIRT2 function in DNA repair and neuronal survival following IR/CisP. We hypothesize that SIRT2 activity, which is suppressed by CDK5-mediated phosphorylation, protects neurons against IR/CisP-induced DNA damage by enhancing CSB- directed TC-NER and TC-HRR, thereby attenuating neuronal cytotoxicity and neurological deficits. A series of in vitro and in vivo experiments are proposed to test this hypothesis:
Aim 1 will determine whether CSB mediates SIRT2 promotion of TC-NER/TC-HRR and neuron survival following IR/CisP.
Aim 2 will determine how CDK5 negatively regulates SIRT2 function in TC- NER/TC-HRR and neuron survival following IR/CisP.
Aim 3 will test if pharmacologically targeting SIRT2 specifically attenuates neuronal deficits following IR/CisP-based cancer therapy. Results from these studies will provide insights into the biological role of SIRT2 and the molecular mechanisms regulating the repair of IR/CisP-induced DNA damage. We expect this study to lay the foundation for future research investigating the targeting of the CDK5/SIRT2-CSB signaling axis as a novel strategy to alleviate and/or prevent neurotoxicity in cancer patients who need IR/CisP therapy.
The consequences of irradiation- and/or Cisplatin (IR/CisP)-induced neurotoxicity, often irreversible and permanent neurological deficits, represent a daunting challenge when treating patients with cancer. This proposal aims to determine the mechanisms protecting neurons from IR/CisP-induced cytotoxicity, with the overarching goal to provide evidence supporting novel strategies to decrease their neurotoxicity, while maintaining therapy efficacy and improving patient quality of life. We expect this study to lay the foundation for future research investigating the targeting of the CDK5/SIRT2-CSB signaling axis as a novel strategy to alleviate and/or prevent neurotoxicity in cancer patients who need IR/CisP therapy.
