Biology subjects

Tretyakova, N. Y.

Publications and source records attributed to Tretyakova, N. Y..

3 recordsLinked to original sources

bioRxiv2026

DNA Adenine Methylation Clock in Brain Aging and Alzheimer's Disease Progression

N6-methyldeoxyadenosine (N6medA) is a recently identified endogenous DNA modification widely found in bacteria, plants, and eukaryotes. In mammals, N6medA has been implicated in brain function, immunity, and response to environmental stress, but its relevance to gene regulation and mammalian aging remains controversial due to its extremely low abundance (< 1 per 10 million adenines) and an uncertainty regarding its genomic origin. We have developed and validated an ultrasensitive isotope dilution nano liquid chromatography-nanospray ionization Orbitrap mass spectrometry methodology to quantify N6medA in genomic DNA. Applying this approach to human prefrontal cortex tissues, we found that genomic N6medA levels increase linearly with chronological age (Pearson correlation coefficient, 0.95). Individuals with mild cognitive impairment (MCI) and Alzheimers disease (AD) exhibited a trend toward elevated cortical N6medA levels relative to age-matched controls. Genome-wide profiling of N6medA in human prefrontal cortex was conducted using two independent methods: NAME-Seq and MeDIP-Seq, which revealed age associated adenine methylation changes reminiscent of established epigenetic aging signatures such as the 5-methylcytosine clocks. N6medA mapping experiments identified a subset of genomic loci that were altered in MCI and AD. Pathway analysis of cross-validated adenine methylation sites revealed an enrichment of genes involved in neuronal function and age-related neurological processes, including glutamatergic synapse, axon guidance, and long-term depression. Finally, mass-spectrometry-based photoaffinity proteomics with synthetic DNA representing a region of the APP gene identified N6medA reader proteins with known roles in DNA repair, replication and transcription. Together, these findings identify N6medA as an age-associated DNA modification in the human brain and suggest that its accumulation and recognition by specific protein readers may contribute to molecular processes underlying brain aging and age-related neurodegeneration.

biochemistry↗

bioRxiv2026

Living Cells Employ Ubiquitin-Proteasomal System and Nucleotide Excision Repair Pathways to Remove Reactive Oxygen Species-Induced DNA-Protein Crosslinks (ROS-DPCs).

Oxidative DNA damage caused by endogenous reactive oxygen species (ROS) is a key driver of mutagenesis, cellular dysfunction, and aging, contributing to diseases like cancer, neurodegeneration, rheumatoid arthritis, cardiovascular disorders, and diabetes. Although more than 20 oxidative base lesions have been identified, ROS-induced DNA-protein crosslinks (DPCs) are poorly characterized. ROS-DPCs are unusually bulky and highly toxic lesions that accumulate in metabolically active tissues with age, but their identities, biological consequences, and repair in living cells have remained elusive. In the present work, we characterized ROS-DPCs in human fibrosarcoma (HT1080) cells treated with hydrogen peroxide (H2O2) and elucidated the mechanisms of their removal. Mass spectrometry-based proteomics has identified over 100 cellular proteins that participated in DPC formation, most of which are involved in DNA metabolism. Our data further reveal that DNA replication and transcription facilitate DPC detection and identify a critical role of the ubiquitin-proteasomal system (UPS), replication-coupled activity of SPRTN metalloprotease, and nucleotide excision repair (NER) in removing ROS-induced DPCs. ROS-DPC formation was blocked by pretreatment with metabolically stable and cell-permeable glutathione (GSH) analog ({Psi}-GSH), suggesting a possible therapeutic strategy for preventing diseases associated with increased ROS levels. KEY POINTSMass spectrometry-based proteomics identified over 100 proteins participating in DNA-protein cross-links in human cells treated with ROS Our work reveals the mechanisms through which living cells recognize and remove ROS-DPCs Our study demonstrates the potential of a glutathione analog to prevent ROS-DPC formation GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/704426v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@61ea7dorg.highwire.dtl.DTLVardef@69c420org.highwire.dtl.DTLVardef@1cb28aeorg.highwire.dtl.DTLVardef@dbc8d7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2019

DNA epigenetic marks are linked to reproductive aberrations in amphipods

Linking exposure to environmental contaminants with diseases is crucial for proposing preventive and regulatory actions. Upon exposure to anthropogenic chemicals, covalent modifications on the genome can drive developmental and reproductive disorders in wild populations, with subsequent effects on the population persistence. Hence, screening of chemical modifications on DNA can be used to provide information on the probability of such disorders in populations of concern. Using a high-resolution mass spectrometry methodology, we identified DNA nucleoside adducts in gravid females of the Baltic amphipods Monoporeia affinis, and linked the adduct profiles to the frequency of embryo malformations in the broods. Twenty-three putative nucleoside adducts were detected in the females and their embryos, and eight modifications were structurally identified using high-resolution accurate mass data. To identify which adducts were significantly associated with embryo malformations, partial least squares regression (PLSR) modelling was applied. The PLSR model yielded three adducts as the key predictors: methylation at two different positions of the DNA (5-methyl-2-deoxycytidine and N6-methyl-2-deoxyadenosine) representing epigenetic marks, and a structurally unidentified nucleoside adduct. These adducts predicted the elevated frequency of the malformations with a high classification accuracy (84%). To the best of our knowledge, this is the first application of DNA adductomics for identification of contaminant-induced malformations in field-collected animals. The method can be adapted for a broad range of species and evolve as a new omics tool in environmental health assessment.

ecology↗