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SIRT7 Promotes Hepatitis B Virus Transcription via the Upregulation of DDB1 Expression and Facilitation of DDB1 Recruitment to Covalently Closed Circular DNA

Year: 2025

Type: article

Abstract: Background: Transcription of the hepatitis B virus (HBV) is regulated by the acetylation status of H3/H4 histones bound to the covalently closed circular DNA (cccDNA) minichromosome. Thus, this study aimed to investigate whether sirtuin 7 (SIRT7), an NAD⁺-dependent acetylated lysine 18 of histone H3 (H3K18Ac) deacetylase, represses HBV transcription by catalyzing H3K18 deacetylation on the cccDNA minichromosome. Methods: We investigated the effects of SIRT7 overexpression/knockdown on HBV transcription and histone acetylation in HepG2.2.15 cells, which constitutively express HBV, and HBV-infected HepG2-NTCP cells. Viral RNA levels and hepatitis B surface and e antigen levels were quantified using reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Meanwhile, Western blotting was used to determine protein expression levels. The association between DNA damage-binding protein 1 (DDB1) and cccDNA and the acetylation status of cccDNA minichromosome-associated H3K18 were analyzed using chromatin immunoprecipitation. Co-immunoprecipitation was used to detect protein–protein interactions. Data were statistically analyzed using Student’s t-test. Results: This study demonstrated that SIRT7 enhanced rather than repressed HBV transcription. Mechanistically, SIRT7 promoted HBV transcription by upregulating DDB1, a protein essential for HBV transcription, and by facilitating the recruitment of DDB1 to the cccDNA minichromosome. SIRT7 knockdown inhibited DDB1 expression and reduced DDB1 enrichment on the cccDNA, thereby suppressing HBV transcription. Conversely, SIRT7 overexpression upregulated DDB1 expression and enhanced DDB1–cccDNA binding, eventually promoting HBV transcription. Conclusions: SIRT7 enhances HBV transcription by upregulating DDB1 expression and promoting an association between DDB1 and cccDNA.

Source: Frontiers in Bioscience-Landmark

DOI: 10.31083/fbl46445