Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Su, Mei-Tzu; Liu, I-Hua; Wu, Chien‐Wei; Chang, Shu-Ming; Tsai, Ching-Hwa; Yang, Po-Chun; Chuang, Yu-Chia; Lee, Chung-Pei; Chen, Mei‐Ru

doi:10.1128/jvi.00950-14

Cited by 35 publications

(69 citation statements)

References 69 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reactivation is also reduced in human gammaherpesvirus latency cell systems lacking the EBV viral UNG (BKRF3) alone or in the absence of both the vUNG and the host UNG (13,18,(37)(38)(39). Interestingly, Su et al (13) recently reported that host UNG2 levels decrease as EBV reactivation proceeds, indicating that the viral UNG is needed to promote replication under conditions of low host UNG levels (13). We attribute the lack of a reactivation defect for MHV68 ⌬UNG to the latency reservoir under analysis at 16 to 18 dpi: actively proliferating peritoneal exudate cells or germinal center CD95…”

Section: Discussionmentioning

confidence: 99%

“…However, HSV-1 reactivation was measured post-explant from trigeminal ganglia: a tissue composed of terminally differentiated adult neurons with low levels of host UNG (18,36). Reactivation is also reduced in human gammaherpesvirus latency cell systems lacking the EBV viral UNG (BKRF3) alone or in the absence of both the vUNG and the host UNG (13,18,(37)(38)(39). Interestingly, Su et al (13) recently reported that host UNG2 levels decrease as EBV reactivation proceeds, indicating that the viral UNG is needed to promote replication under conditions of low host UNG levels (13).…”

Section: Discussionmentioning

confidence: 99%

“…Our data clearly demonstrate an important role for the vUNG in virus replication in the lung that is largely devoid of host UNG, and yet the mechanisms by which the host and viral UNGs contribute to gammaherpesvirus replication are not well characterized. The EBV and HSV-1 vUNG (UL2) promote viral DNA replication (13,15,41). Interaction of the HSV-1 origin binding protein with the Ori S is impaired by the presence of uracils in the target sequence (42).…”

Section: Discussionmentioning

confidence: 99%

“…Mutation of the human cytomegalovirus (HCMV) vUNG (UL114) delays HCMV replication in cell culture (14,15). Epstein-Barr virus (EBV) DNA synthesis is reduced upon reactivation from latency in the absence of the vUNG (BKRF3) (13). Moreover, herpes simplex virus 1 (HSV-1) vUNG (UL2) mediates base-excision repair in vitro (16) and loss of UL2 alone or together with loss of the HSV-1 dUTPase results in increased mutation rates upon serial passaging in culture (9).…”

mentioning

confidence: 99%

“…Viral UNGs (vUNGs) interact with components of the viral DNA replication machinery, including viral DNA polymerases and lytic gene transactivators (11)(12)(13). Mutation of the human cytomegalovirus (HCMV) vUNG (UL114) delays HCMV replication in cell culture (14,15).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Minkah

Macaluso

Oldenburg

et al. 2015

J Virol

View full text Add to dashboard Cite

Uracil DNA glycosylases (UNG) are highly conserved proteins that preserve DNA fidelity by catalyzing the removal of mutagenic uracils. All herpesviruses encode a viral UNG (vUNG), and yet the role of the vUNG in a pathogenic course of gammaherpesvirus infection is not known. First, we demonstrated that the vUNG of murine gammaherpesvirus 68 (MHV68) retains the enzymatic function of host UNG in an in vitro class switch recombination assay. Next, we generated a recombinant MHV68 with a stop codon in ORF46/UNG (⌬UNG) that led to loss of UNG activity in infected cells and a replication defect in primary fibroblasts. Acute replication of MHV68⌬UNG in the lungs of infected mice was reduced 100-fold and was accompanied by a substantial delay in the establishment of splenic latency. Latency was largely, yet not fully, restored by an increase in virus inoculum or by altering the route of infection. MHV68 reactivation from latent splenocytes was not altered in the absence of the vUNG. A survey of host UNG activity in cells and tissues targeted by MHV68 indicated that the lung tissue has a lower level of enzymatic UNG activity than the spleen. Taken together, these results indicate that the vUNG plays a critical role in the replication of MHV68 in tissues with limited host UNG activity and this vUNG-dependent expansion, in turn, influences the kinetics of latency establishment in distal reservoirs. IMPORTANCEHerpesviruses establish chronic lifelong infections using a strategy of replicative expansion, dissemination to latent reservoirs, and subsequent reactivation for transmission and spread. We examined the role of the viral uracil DNA glycosylase, a protein conserved among all herpesviruses, in replication and latency of murine gammaherpesvirus 68. We report that the viral UNG of this murine pathogen retains catalytic activity and influences replication in culture. The viral UNG was impaired for productive replication in the lung. This defect in expansion at the initial site of acute replication was associated with a substantial delay of latency establishment in the spleen. The levels of host UNG were substantially lower in the lung compared to the spleen, suggesting that herpesviruses encode a viral UNG to compensate for reduced host enzyme levels in some cell types and tissues. These data suggest that intervention at the site of initial replicative expansion can delay the establishment of latency, a hallmark of chronic herpesvirus infection.A ll herpesvirus genomes encode a homolog of the host uracil DNA glycosylase. If not repaired, uracil misincorporation during DNA replication (1, 2) or conversion upon cytosine deamination (2, 3) will lead to a C:G-to-T:A transition mutation that may have severe consequences for genomic integrity (1). In the host, the recognition and removal of uracils is mediated by members of the uracil DNA glycosylase (UDG) superfamily. UNG2 is the predominant nuclear enzyme responsible for initiating repair (2-6). The role of a seemingly redundant herpesvirus UNG in viral replication is ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Minkah

Macaluso

Oldenburg

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

Encyclopedia of EBV-Encoded Lytic Genes: An Update

Murata

2018

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

In addition to latent genes, lytic genes of EBV must also be of extreme significance since propagation of the virus can be achieved only through execution of lytic cycle. Research on EBV lytic genes may thus prevent spreading of the virus and alleviate disorders, such as infectious mononucleosis and oral hairy leukoplakia, which are highly associated with EBV lytic infection. Moreover, recent advancements have been demonstrating that at least several lytic genes are expressed to some extent even during latent state. It is also demonstrated now that upon de novo infection, EBV expresses lytic genes in addition to latent genes before establishment of latency (this phase is called "pre-latent abortive lytic state"). In those cases, lytic genes also play important roles in cell proliferation of EBV-positive cells. However, many lytic gene products have not been identified yet nor studied thoroughly, and even worse, some have been misidentified in the literature. Here, I would like to give a detailed up-to-date review on EBV lytic genes.

show abstract