期刊
LIFE SCIENCE ALLIANCE
卷 2, 期 2, 页码 -出版社
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.201900355
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资金
- EU 2020 Research and Innovation Programme Consortia HEP-CAR [667273]
- Wellcome Trust [IA 200838/Z/16/Z, IA 100954]
- MRC project [MR/R022011/1]
- Lister Institute Summer studentship
- MRC Career Development Fellowship [MR/P009085/1]
- Birmingham Fellowship - University of Birmingham
- UK Medical Research Council (MRC core funding of the MRC Human Immunology Unit)
- Wellcome Trust Infection and Immunology & Translational Medicine doctoral programme [105400/Z/14/Z]
- MRC/MHU [MC-UU-12009]
- John Fell Fund [123/737]
- WIMM Strategic Alliance [G0902418, MC_UU_12025]
- German Research Foundation via the collaborative research center [TRR179, TP14]
- Institute for Advanced Study
- Technical University of Munich via the German Excellence Initiative
- EU 7th Framework Program [291763]
- Wellcome Trust [105400/Z/14/Z] Funding Source: Wellcome Trust
- BBSRC [BB/N008553/2, BB/N008553/1] Funding Source: UKRI
- MRC [G0400802, MR/R022011/1, G0801976, G1100247, MC_UU_00008/8, MR/P009085/1] Funding Source: UKRI
Chronic hepatitis B is one of the world's unconquered diseases with more than 240 million infected subjects at risk of developing liver disease and hepatocellular carcinoma. Hepatitis B virus reverse transcribes pre-genomic RNA to relaxed circular DNA (rcDNA) that comprises the infectious particle. To establish infection of a naive target cell, the newly imported rcDNA is repaired by host enzymes to generate covalently closed circular DNA (cccDNA), which forms the transcriptional template for viral replication. SAMHD1 is a component of the innate immune system that regulates deoxyribonucleoside triphosphate levels required for host and viral DNA synthesis. Here, we show a positive role for SAMHD1 in regulating cccDNA formation, where KO of SAMHD1 significantly reduces cccDNA levels that was reversed by expressing wild-type but not a mutated SAMHD1 lacking the nuclear localization signal. The limited pool of cccDNA in infected Samhd1 KO cells is transcriptionally active, and we observed a 10-fold increase in newly synthesized rcDNA-containing particles, demonstrating a dual role for SAMHD1 to both facilitate cccDNA genesis and to restrict reverse transcriptase-dependent particle genesis.
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