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Translesion Synthesis DNA Polymerase Kappa Is Indispensable for DNA Repair Synthesis in Cisplatin Exposed Dorsal Root Ganglion Neurons

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Abstract

In the peripheral nervous system (PNS) in the absence of tight blood barrier, neurons are at increased risk of DNA damage, yet the question of how effectively PNS neurons manage DNA damage remains largely unanswered. Genotoxins in systemic circulation include chemotherapeutic drugs that reach peripheral neurons and damage their DNA. Because neurotoxicity of platinum-based class of chemotherapeutic drugs has been implicated in PNS neuropathies, we utilized an in vitro model of Dorsal Root Ganglia (DRGs) to investigate how peripheral neurons respond to cisplatin that forms intra- and interstrand crosslinks with their DNA. Our data revealed strong transcriptional upregulation of the translesion synthesis DNA polymerase kappa (Pol κ), while expression of other DNA polymerases remained unchanged. DNA Pol κ is involved in bypass synthesis of diverse DNA lesions and considered a vital player in cellular survival under injurious conditions. To assess the impact of Pol κ deficiency on cisplatin-exposed DRG neurons, Pol κ levels were reduced using siRNA. Pol κ targeting siRNA diminished the cisplatin-induced nuclear Pol κ immunoreactivity in DRG neurons and decreased the extent of cisplatin-induced DNA repair synthesis, as reflected in reduced incorporation of thymidine analog into nuclear DNA. Moreover, Pol κ depletion exacerbated global transcriptional suppression induced by cisplatin in DRG neurons. Collectively, these findings provide the first evidence for critical role of Pol κ in DNA damage response in the nervous system and call attention to implications of polymorphisms that modify Pol κ activity, on maintenance of genomic integrity and neuronal function in exogenously challenged PNS.

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Abbreviations

Pol κ:

DNA polymerase kappa

BER:

Base excision repair

DRG:

Dorsal root ganglion

NER:

Nucleotide excision repair

PNS:

Peripheral nervous system

TLS:

Translesion synthesis

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Acknowledgements

This work was supported by grants from the National Institutes of Health (ES014613) and Shriners Hospitals for Children (86700) and Surgery Department at UTMB to EWE. We thank Steve Schuenke and Eileen Figueroa for assistance with manuscript preparation.

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  1. Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA

    Ming Zhuo, Murat F. Gorgun & Ella W. Englander

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  1. Ming Zhuo
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  2. Murat F. Gorgun
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  3. Ella W. Englander
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Correspondence to Ella W. Englander.

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Ming Zhuo and Murat F. Gorgun are the co-first authors

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Zhuo, M., Gorgun, M.F. & Englander, E.W. Translesion Synthesis DNA Polymerase Kappa Is Indispensable for DNA Repair Synthesis in Cisplatin Exposed Dorsal Root Ganglion Neurons. Mol Neurobiol 55, 2506–2515 (2018). https://doi.org/10.1007/s12035-017-0507-5

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