# The novel role of Sirtuin 2 in regulation of transcription-associated DNA damage repair

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2021 · $179,364

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 10122925
- **Project number:** 5R01CA247947-02
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Fen Xia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $179,364
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122925

## Citation

> US National Institutes of Health, RePORTER application 10122925, The novel role of Sirtuin 2 in regulation of transcription-associated DNA damage repair (5R01CA247947-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122925. Licensed CC0.

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