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• W4387136503 abstract "Abstract Genomic stability is critical for cellular function, however, postmitotic cells such as highly metabolically active neurons face the biggest challenge as they must maintain their genome over an organismal lifetime. DNA damage in neurons increases with chronological age and is accelerated in Alzheimer’s disease, and neurodegenerative disorders, resulting in downstream cellular and systemic dysregulation. Distinct DNA damage response pathways have evolved with a host of distinct polymerases that act via different pathways such as nucleotide excision repair, and base excision repair to mend DNA lesions. The Y-family polymerases are known for their key role in bypassing damaged DNA through the process of translesion synthesis in dividing cells, however, their functions in enduring post-mitotic cell types like neurons are largely unknown. We show that one such member of the Y-family polymerases, DNA polymerase kappa protein (POLK), is subcellularly localized in the nucleus and cytoplasm of neurons. With chronological age, there is a significant reduction of nuclear POLK and a concomitant accumulation in the cytoplasm. The reduction of nuclear POLK in old brains is congruent with an increase in nuclear DNA damage. We further report that nuclear POLK expression is not uniform among cell types in the brain with significantly higher levels of nuclear POLK in GABAergic interneurons compared to excitatory pyramidal neurons and non-neurons, possibly reflective of the inherent biological differences such as axonal projection, neuronal activity, and their firing rates. Due to the non-replicative status of differentiated neurons in mature circuits, it is critical to understand the different repair strategies and mechanisms that postmitotic neurons employ to maintain their genomic integrity, which will help design therapies for human longevity and the prevention of neurodegeneration." @default.
• W4387136503 created "2023-09-29" @default.
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• W4387136503 date "2023-09-28" @default.
• W4387136503 modified "2023-10-05" @default.
• W4387136503 title "An altered cell type-specific subcellular distribution of translesion synthesis DNA polymerase kappa (PolK) in aging neurons" @default.
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• W4387136503 doi "https://doi.org/10.1101/2023.09.27.559771" @default.
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