Polymerases and DNA Repair in Neurons: Implications in Neuronal Survival and Neurodegenerative Diseases

Abstract

Most of the neurodegenerative diseases and aging are associated with reactive oxygen species (ROS) or other intracellular damaging agents that challenge the genome integrity of the neurons. As most of the mature neurons stay in G0/G1 phase, replication-uncoupled DNA repair pathways including BER, NER, SSBR, and NHEJ, are pivotal, efficient, and economic mechanisms to maintain genomic stability without reactivating cell cycle. In these progresses, polymerases are prominent, not only because they are responsible for both sensing and repairing damages, but also for their more diversified roles depending on the cell cycle phase and damage types. In this review, we summarized recent knowledge on the structural and biochemical properties of distinct polymerases, including DNA and RNA polymerases, which are known to be expressed and active in nervous system; the biological relevance of these polymerases and their interactors with neuronal degeneration would be most graphically illustrated by the neurological abnormalities observed in patients with hereditary diseases associated with defects in DNA repair; furthermore, the vicious cycle of the trinucleotide repeat (TNR) and impaired DNA repair pathway is also discussed. Unraveling the mechanisms and contextual basis of the role of the polymerases in DNA damage response and repair will promote our understanding about how long-lived postmitotic cells cope with DNA lesions, and why disrupted DNA repair contributes to disease origin, despite the diversity of mutations in genes. This knowledge may lead to new insight into the development of targeted intervention for neurodegenerative diseases.

Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues

“…While the brain in general is of increasing interest in DNA repair syndromes, the cerebellum seems to be especially vulnerable to impaired BER and single‐strand break repair (Li et al, 2022; Narciso et al, 2016). Therefore, the nonradioactive assay for determination of DNA ligation efficiency in murine tissue samples was first established in cerebellum tissue.…”

“…While the brain in general is of increasing interest in DNA repair syndromes, the cerebellum seems to be especially vulnerable to impaired BER and single-strand break repair (Li et al, 2022;Narciso et al, 2016).…”

Effect of Exercise and Oral Niacinamide Mononucleotide on Improving Mitochondrial Autophagy in Alzheimer’s Disease

“…In the latest study by Rasti et al, SIRT1 was the main factor of DNA damage response and DNA repair, autophagy could also be understood as a response to DNA damage, and autophagy was affected by SIRT1 deacetylation. SIRT1 signaling to DNA damage through PP4 ensures the normal progress of DNA damage repair, which will be beneficial to neuronal regeneration [ 74 , 75 , 76 ]. SIRT1 plays an important role in AD, especially in the regulation of mitochondrial homeostasis through deacetylation [ 77 ].…”