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bioRxiv · 10.1101/2022.05.20.492761

Sustained pigmentation causes DNA damage and invokes translesion polymerase Pol κ for repair in melanocytes

Natarajan, V.·Khanna, S.·Ghazi, M.·Subramaniam, Y. J.·Gupta, I.·Sultan, F.·Sharma, K.·Chandna, S.·Gokhale, R. S.
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Abstract

The pigment melanin protects skin cells from ultraviolet (UV) radiation induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases DNA damage, causes cell cycle arrest, and invokes translesion polymerase Pol {kappa} for DNA repair in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase, the key melanin synthesizing enzyme results in depigmented cells with low Pol {kappa} levels. However, silencing of Pol {kappa} in pigmenting cells results in unchecked proliferation despite the presence of damaged DNA, that could potentially lead to genome instability. Thereby, our results indicate Pol {kappa} to be a necessary evil to resolve melanin induced damage. Error-prone repair by Pol {kappa} in part explains the mutational landscape observed in human melanoma. Thus, our study illuminates a hitherto unknown dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis mediated via the Pol {kappa}-based low fidelity DNA repair response of melanocytes. Key HighlightsO_LISustained melanogenesis causes DNA damage in melanocytes C_LIO_LIMelanogenesis elicits replication stress and translesion repair by Pol {kappa} C_LIO_LIPol {kappa} resolves melanin-induced DNA damage and suppresses genome instability C_LIO_LIExpression of Pol {kappa} correlates with mutational load in human melanoma C_LI

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Natarajan, V., Khanna, S., Ghazi, M., Subramaniam, Y. J., Gupta, I., Sultan, F., Sharma, K., Chandna, S., Gokhale, R. S.. 2022-05-25. Sustained pigmentation causes DNA damage and invokes translesion polymerase Pol κ for repair in melanocytes. https://doi.org/10.1101/2022.05.20.492761

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