Epstein-Barr virus BNRF1 destabilizes SMC5/6 cohesin complexes to evade its restriction of replication compartments

Yiu, Stephanie Pei Tung; Guo, Rui; Zerbe, Cassie; Weekes, Michael P.; Gewurz, Benjamin E.

doi:10.1016/j.celrep.2022.110411

Cited by 45 publications

(32 citation statements)

References 87 publications

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“…Lastly, the SMC5-SMC6 complex, which is critical for genome stability and DNA repair 36 , has emerged as a component of antiviral responses. It has recently been linked to transcriptional restriction of numerous DNA viruses, such as hepatitis B virus, unintegrated retroviral DNA, papillomavirus and Epstein-Barr virus [37][38][39][40] . Our data suggests that SMC5-SMC6 can also potently inhibit rAAV vectors.…”

Section: Discussionmentioning

confidence: 99%

Genome-scale analysis of cellular restriction factors that inhibit transgene expression from adeno-associated virus vectors

Ngo

Puschnik

2022

Preprint

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Adeno-associated virus (AAV) vectors are one of the leading platforms for gene delivery for the treatment of human genetic diseases, but the antiviral cellular mechanisms that interfere with optimal transgene expression are incompletely understood. Here, we performed two genome-scale CRISPR screens to identify cellular factors that restrict transgene expression from AAV vectors. Our screens revealed several components linked to DNA damage response, chromatin remodeling and transcriptional regulation. Inactivation of the Fanconi Anemia gene FANCA, the Human Silencing Hub (HUSH) associated methyltransferase SETDB1 and the gyrase, Hsp90, histidine kinase and MutL (GHKL)-type ATPase MORC3 led to increased transgene expression. Moreover, SETDB1 and MORC3 knockout improved transgene levels of several AAV serotypes as well as other viral vectors, such as Lentivirus and Adenovirus. Finally, we demonstrated that siRNA knockdown of SETDB1 and MORC3 prior to viral vector administration enhanced transgene expression, providing a strategy for the improvement of gene therapy applications.

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Section: Discussionmentioning

confidence: 99%

Genome-scale analysis of cellular restriction factors that inhibit transgene expression from adeno-associated virus vectors

Ngo

Puschnik

2022

Preprint

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“…Humanized mice immunized with these EBNA-1-VLPs were successfully protected against EBV challenge 104 . However, except for latent proteins, BNRF1 and viral particles can also induce genetic instability and chromosome defects in infected cells 105 , 106 . Hence, safety evaluation of genetic instability and chromosome defects is needed for VLPs generated from non-transforming, virus-free packaging cell lines.…”

Section: Where Are We Now?mentioning

confidence: 99%

Urgency and necessity of Epstein-Barr virus prophylactic vaccines

et al. 2022

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Epstein-Barr virus (EBV), a γ-herpesvirus, is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them was able to prevent EBV infection and no vaccine has been approved to date. Current efforts focus on antigen selection, combination, and design to improve the efficacy of vaccines. EBV glycoproteins such as gH/gL, gp42, and gB show excellent immunogenicity in preclinical studies compared to the previously favored gp350 antigen. Combinations of multiple EBV proteins in various vaccine designs become more attractive approaches considering the complex life cycle and complicated infection mechanisms of EBV. Besides, rationally designed vaccines such as virus-like particles (VLPs) and protein scaffold-based vaccines elicited more potent immune responses than soluble antigens. In addition, humanized mice, rabbits, as well as nonhuman primates that can be infected by EBV significantly aid vaccine development. Innovative vaccine design approaches, including polymer-based nanoparticles, the development of effective adjuvants, and antibody-guided vaccine design, will further enhance the immunogenicity of vaccine candidates. In this review, we will summarize (i) the disease burden caused by EBV and the necessity of developing an EBV vaccine; (ii) previous EBV vaccine studies and available animal models; (iii) future trends of EBV vaccines, including activation of cellular immune responses, novel immunogen design, heterologous prime-boost approach, induction of mucosal immunity, application of nanoparticle delivery system, and modern adjuvant development.

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“…More recently, SMC and SMC-like complexes have also been implicated in bacterial immunity against plasmids (Doron et al, 2018;Jaskolska et al, 2022;Panas et al, 2014). A putatively related function in viral restriction against HBV, EBV, KSHV, and HIV-1 has been reported for the Smc5/6 complex in human cells (Decorsiere et al, 2016;Dupont et al, 2021;Han et al, 2022;Murphy et al, 2016;Yiu et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

DNA-measuring Wadjet SMC ATPases restrict smaller circular plasmids by DNA cleavage

Liu

Roisné-Hamelin

Beckert

et al. 2022

Preprint

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Structural maintenance of chromosomes (SMC) complexes fold DNA by loop extrusion to support chromosome segregation, genome maintenance, and gene expression. Wadjet systems (JetABCD/MksBEFG/EptABCD) are derivative SMC complexes with proposed roles in bacterial immunity against selfish DNA elements. Here, we show that JetABCD systems restrict extrachromosomal circular DNA with an upper size limit of about 100 kb, while a linear plasmid evades restriction. Recombinant preparations of a JetABCD complex cleave circular DNA regardless of its helical topology but not linear DNA; cleavage occurs at random positions and depends on ATP as well as the SMC ATPase. We solve a structure of the JetABCD core by cryo-EM revealing an alternative dimer-of-dimers configuration. The two SMC DNA motor units face in opposite orientations - rather than the same as observed with MukBEF - possibly representing a restriction-specific state of JetABCD. We hypothesize that JetABCD is a DNA-shape-specific endonuclease and present a model for the activation of DNA cleavage exclusively when extrusion of an entire plasmid has been completed by a single JetABCD complex. The self-stalling of two opposing DNA motor units may serve as signal to trigger DNA cleavage. Complete extrusion by a single complex cannot be achieved on the much larger chromosome, explaining how self-DNA may evade cleavage.

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Epstein-Barr virus BNRF1 destabilizes SMC5/6 cohesin complexes to evade its restriction of replication compartments

Cited by 45 publications

References 87 publications

Genome-scale analysis of cellular restriction factors that inhibit transgene expression from adeno-associated virus vectors

Genome-scale analysis of cellular restriction factors that inhibit transgene expression from adeno-associated virus vectors

Urgency and necessity of Epstein-Barr virus prophylactic vaccines

DNA-measuring Wadjet SMC ATPases restrict smaller circular plasmids by DNA cleavage

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