Biology subjects

Boldogh, I.

Publications and source records attributed to Boldogh, I..

3 recordsLinked to original sources

bioRxiv2026

OGG1-Binding to Oxidized Guanine Base in Viral DNA Overcomes Epstein-Barr Virus Latency

Epstein-Barr virus (EBV) establishes lifelong latency in human cells and can periodically reactivate, contributing to several cancers. However, the molecular mechanisms that disrupt EBV latency, particularly those driven by oxidative stress, require further investigation. In this study, we provide evidence that oxidative DNA damage, particularly the formation of 8-oxoguanine and its repair enzyme OGG1, is involved in EBV reactivation. We demonstrated that OGG1 is recruited to EBV regulatory regions under oxidative stress conditions and is associated with the transcriptional activation of immediate-early and early lytic genes. Further experiments showed that pharmacological inhibition of OGG1 DNA binding significantly suppressed EBV lytic gene expression, supporting a functional role for OGG1 in viral reactivation. Mechanistically, our findings suggest that OGG1 may contribute to EBV lytic activation through a noncanonical mechanism independent of its glycosylase activity. These findings provide insight into how EBV may exploit host oxidative DNA damage responses to facilitate latency disruption and suggest that targeting OGG1 may offer a potential strategy to limit EBV reactivation and EBV-associated diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/728896v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@7866a7org.highwire.dtl.DTLVardef@9b5f35org.highwire.dtl.DTLVardef@87a87aorg.highwire.dtl.DTLVardef@461005_HPS_FORMAT_FIGEXP M_FIG C_FIG The model illustrates how oxidative DNA damage promotes Epstein-Barr virus (EBV) lytic reactivation through host base excision repair machineryReactive oxygen species (ROS) may induce oxidative modification of guanine to 8-oxoguanine (8-oxoGua) in latent EBV genomes, potentially contributing to OGG1 recruitment to viral regulatory regions. OGG1 binding facilitates the transcriptional activation of immediate-early and early lytic genes, likely through transcription factor recruitment, thereby contributing to the transition from latency to lytic replication. Pharmacological inhibition of OGG1-DNA interaction suppresses this process, highlighting OGG1 as a potential therapeutic target. 8-oxoGua, 7,8-dihydro-8-oxoguanine; OGG1, 8-oxoguanine DNA glycosylase-1. Significance StatementO_LIidentifies a potential mechanism by which ROS-induced oxidative DNA base damage and OGG1 recruitment within the EBV genome may contribute to viral reactivation from latency. C_LIO_LIsuggests that oxidative DNA repair intermediates may serve as regulatory platforms for viral gene expression. C_LIO_LIprovides pharmacological evidence supporting OGG1 as a potential therapeutic target for suppressing EBV reactivation. C_LI

microbiology↗

bioRxiv2023

Site-specific acetylation of polynucleotide kinase 3-phosphatase (PNKP) regulates its distinct role in DNA repair pathways

Mammalian polynucleotide kinase 3-phosphatase (PNKP) is a dual-function DNA end-processing enzyme with 3-phosphatase and 5-kinase activities, which generate 3-OH and 5-phosphate termini respectively, as substrates for DNA polymerase and DNA ligase to complete DNA repair. PNKP is thus involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes, which involve distinct sets of proteins. In this study, we report that PNKP is acetylated at two lysine (K142 and K226) residues. While K142 (AcK142) is constitutively acetylated by p300, CBP acetylates K226 (AcK226) only after DSB induction. Co-immunoprecipitation analysis using antibodies specific for PNKP peptides containing AcK142 or AcK226 of PNKP showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP only with DSBR proteins. Although acetylation at these residues did not significantly affect the enzymatic activity of PNKP in vitro, cells expressing non-acetylable PNKP (K142R or K226R) accumulated DNA damage, specifically in transcribed genes. Intriguingly, in striatal neuronal cells of a Huntingtons Disease (HD)-based mouse model, K142, but not K226, was acetylated. This observation is consistent with the reported degradation of CBP but not p300 in HD cells. Moreover, genomes of HD cells progressively accumulated DSBs specifically in the transcribed genes. Chromatin-immunoprecipitation analysis using anti-AcK142 or anti-AcK226 antibodies demonstrated an association of Ac-PNKP with the transcribed genes, consistent with PNKPs role in transcription-coupled repair. Thus, our findings collectively demonstrate that acetylation at two lysine residues located in different domains of PNKP regulates its functionally distinct role in BER/SSBR vs. DSBR.

biochemistry↗

bioRxiv2022

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

Allergic asthma is a complex disease characterized by dyspnea, coughing, chest tightness and airway remodeling, for which there is no cure and is symptomatically treated with inhaled {beta}2-agonist and/or corticosteroids. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, the 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammatory responses. In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-{kappa}B and expression of proinflammatory cytokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed down regulation of Arg1, Mcp1 and Ccl11, and upregulation of the negative regulator of TH2, Bcl6. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Taken together, the data presented in this study suggest a clinically relevant utilization of TH5487 for the treatment of allergic inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/492235v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@2985cdorg.highwire.dtl.DTLVardef@f642corg.highwire.dtl.DTLVardef@79bb1aorg.highwire.dtl.DTLVardef@1eab483_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗