Mutagenicity of Ochratoxin A: Role for a Carbon-Linked C8–Deoxyguanosine Adduct?

Abstract

Ochratoxin A (OTA) is a fungal toxin that is considered to be a potent kidney carcinogen in rodent models. The toxin produces double strand breaks and has a propensity for deletions, single-base substitutions, and insertions. The toxin reacts covalently with DNA to afford a C8-2'-deoxyguanosine carbon-linked adduct (OT-dG) as the major lesion in animal tissues. Incorporation of model C-linked C8-aryl-dG adducts into the G3 site of the NarI sequence demonstrates a tendency to induce base substitutions and deletion mutations in primer extension assays using model polymerases. The degree of misincorporation induced by the C-linked C8-dG adducts correlates with an ability to adopt the promutagenic syn conformation within the NarI duplex as predicted by molecular dynamics (MD) simulations. MD simulations of the OT-dG adduct within the NarI duplex predict an even greater degree of conformational flexibility, suggesting enhanced in vitro mutagenicity compared to the simpler model C-linked C8-dG adducts. Together these findings support the role of OT-dG in promoting OTA-mediated mutagenicity and carcinogenicity in animal studies.

Molecular Dynamics Simulations of Mismatched DNA Duplexes Associated with the Major C8-Linked 2′-Deoxyguanosine Adduct of the Food Mutagen Ochratoxin A: Influence of Opposing Base, Adduct Ionization State, and Sequence on the Structure of Damaged DNA

“…Molecular dynamics (MD) simulations on damaged DNA is a useful approach for gaining structural insights into the role of adduct formation in the associated mutagenicity. Specifically, MD simulations permit the study of DNA structural dynamics, which can be further used to explain experimental observations. − Therefore, as a first step toward understanding the impact of OTA exposure on DNA structure, we previously employed MD simulations to characterize the conformational preferences of DNA containing the OT-G adduct. , The adduct was paired against complementary cytosine in a DNA oligomer containing the Nar I recognition sequence (5′-G 1 G 2 CG 3 CC), which is the known hotspot for mutations induced by other carcinogenic C 8 -G adducts . Our analysis revealed that OTA-damaged DNA likely adopts a mixture of three distinct (i.e., the major groove (B), wedge (W), and base-displaced intercalated (S)) conformations (Figure B–D) regardless of the adduct ionization state and the lesion-site sequence context.…”

Carrying Excess Baggage Can Slowdown Life: Protein Clearance Machineries That Go Awry During Aging and the Relevance of Maintaining Them

“…There are various health benefits of sleep, including the maintenance of many cellular processes and memory-related function [142]. With aging, sleep quality also decreases and inferior sleep quality is usually related to many age-associated neurodegenerative diseases like AD and PD [98] which are further associated with failure of proteostasis network that brings a question that whether there is any direct correlation of proteostasis with sleeping behavior.…”

Sleep, Aging, and Cellular Health: Aged-Related Changes in Sleep and Protein Homeostasis Converge in Neurodegenerative Diseases

“…The quality of sleep changes across the healthy aging process. In general, as humans reach maturity, some studies suggest that sleep need decreases (Manderville and Wetmore, 2017). Across aging, there are key changes in sleep architecture.…”

“…While the specific functions of sleep are still actively researched, some benefits of sleep, including memory consolidation (Stickgold and Walker, 2007; Diekelmann and Born, 2010) and management of cellular processes (Benington and Heller, 1995; Cirelli et al, 2004), have been demonstrated. However, it is known that sleep quality decreases with age (Manderville and Wetmore, 2017) and poor sleep is often a symptom of many aged-related neurodegenerative diseases, such as Alzheimer’s disease (AD; Ju et al, 2013). This begs the question to what extent is sleep causally related to the progression of aging and the symptoms of neurodegeneration.…”