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Herpes simplex virus 1 (HSV-1) R-loops are targets for APOBEC-mediated innate immunity [RNaseH_DRIP-seq]

ABSTRACT: APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.

ORGANISM(S): Human alphaherpesvirus 1

PROVIDER: GSE284474 | GEO | 2026/03/11

REPOSITORIES: GEO

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Herpes simplex virus 1 (HSV-1) R-loops are targets for APOBEC-mediated innate immunity [DRIP-seq]

Project description:APOBEC cytidine deaminase enzymes play a crucial role in antiviral innate immunity as they introduce mutations in viral genomes, restrict viral replication, and promote host defense against infections. Special three-stranded nucleic acid structures, called R-loops, have been considered as efficient targets for APOBEC-mediated mutagenesis because they present an ideal substrate, a persistent single-stranded DNA, for the enzyme. However, the relationship between R-loops and APOBEC enzyme activity has not been verified and remains to be elucidated. Here, we reveal a mechanistic link between R-loop formation, APOBEC enzyme binding, and APOBEC mutagenesis at viral R-loop targets during virus infection. In a cellular model involving human T lymphoblastoid leukemia cells infected with Herpes simplex virus 1 (HSV-1), we show that APOBEC3A and APOBEC3G binding sites and mutagenesis signatures occur mainly in viral R-loop structures. C-to-T mutagenesis primarily targets R-loops, which are specifically concentrated in HSV-1 genes that are essential for virus assembly and function. Among these genes, we identified mutation hotspots resulting in amino acid changes, likely leading to inactivation of HSV-1 protein functions. Collectively, our findings show that viral R-loops serve as potent targets for APOBEC-induced mutagenesis, representing an effective strategy to inactivate essential viral proteins and compromise viral activity.

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Project description:APOBEC mutagenesis

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