Oxidative stress in cells can lead to accumulation of reactive oxygen species and oxidation of DNA precursors. Oxidized purine nucleotides can be inserted into DNA during replication and repair. The main pathway for correcting oxidized bases in DNA is base excision repair (BER), and in vertebrates DNA polymerase β (pol β) provides gap filling and tailoring functions. Here we report that the DNA ligation step of BER is compromised after pol β insertion of oxidized purine nucleotides into the BER intermediate in vitro. These results suggest the possibility that BER mediated toxic strand breaks are produced in cells under oxidative stress conditions. We observe enhanced cytotoxicity in oxidizing-agent treated pol β expressing mouse fibroblasts, suggesting formation of DNA strand breaks under these treatment conditions. Increased cytotoxicity following MTH1 knockout or treatment with MTH1 inhibitor suggests the oxidation of precursor nucleotides.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228075 | PMC |
| http://dx.doi.org/10.1038/ncomms14045 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ Alzheimer Disease Mouse Model.
J Neurochem
January 2025
The Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Alzheimer disease is a neurodegenerative pathology-modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild-type (Wt) and 3xTgAD-DNA polymerase-β-deficient (3xTg/POLβ) (AD) mice. DNA polymerase-β is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair.
View Article and Find Full Text PDFTemozolomide treatment in refractory pituitary adenomas and pituitary carcinomas.
Neuroendocrinology
January 2025
Background: Temozolomide (TMZ), a non-classical alkylating agent, possesses lipophilic properties that allow it to cross the blood-brain barrier, making it active within the central nervous system. Furthermore, the adverse reactions of the TMZ are relatively mild, which is why it is currently recommended as a first-line chemotherapy drug for refractory pituitary adenomas (RPAs) and pituitary carcinomas (PCs).
Summary: Systematic evaluations indicate a radiological response rate of 41% and a hormonal response rate of 53%, underscoring TMZ clinical efficacy, particularly when combined with radiotherapy.
Design and in vitro anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease.
Nucleic Acids Res
January 2025
School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Ireland.
Copper compounds with artificial metallo-nuclease (AMN) activity are mechanistically unique compared to established metallodrugs. Here, we describe the development of a new dinuclear copper AMN, Cu2-BPL-C6 (BPL-C6 = bis-1,10-phenanthroline-carbon-6), prepared using click chemistry that demonstrates site-specific DNA recognition with low micromolar cleavage activity. The BPL-C6 ligand was designed to force two redox-active copper centres-central for enhancing AMN activity-to bind DNA, via two phenanthroline ligands separated by an aliphatic linker.
View Article and Find Full Text PDFAPOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats.
Proc Natl Acad Sci U S A
January 2025
Program in Genetics, Molecular, and Cellular Biology, Tufts University Graduate School of Biomedical Sciences, Boston, MA 02111.
CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead to inaccurate repair of the repeat tract to cause expansions are not fully understood. Expansion-prone CAG/CTG repeats are actively transcribed and prone to forming stable R-loops with hairpin structures forming on the displaced single-stranded DNA (S-loops).
View Article and Find Full Text PDFBeyond Nucleotide Excision Repair: The Importance of XPF in Base Excision Repair and Its Impact on Cancer, Inflammation, and Aging.
Int J Mol Sci
December 2024
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5'-Gap pathway.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!