An ATM/Chk2-mediated DNA damage responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells

Nikitin, Pavel A.; Yan, Chris; Forte, Eleonora; Bocedi, Alessio; Tourigny, Jay; Patel, Amee B.; Davé, Sandeep S.; Hu, Katherine; Guo, Jing; Tainter, David M.; Rusyn, Olena; Luftig, Micah A.

doi:10.1186/1750-9378-5-s1-a4

Cited by 29 publications

(51 citation statements)

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“…82 Undoubtedly, senescence is an important host defense mechanism against oncogenic virus effects. 83 Recent studies highlight the link between cytosolic DNA sensing and the induction of cellular senescence, stressing the pivotal role of the cGAS-STING pathway, thus, providing the molecular basis for considering cellular senescence as a defense system against virus infection, as well as genomic/neoplastic insult. [84][85][86][87] Accordingly, type I IFNs result protective against retrotransposition events 88 and cells accumulating DNA damage produce endogenous IFN-and become senescent.…”

Section: Type I Interferons At the Crossroad Between Senescent And Vimentioning

confidence: 99%

Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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Section: Type I Interferons At the Crossroad Between Senescent And Vimentioning

confidence: 99%

Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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“…Immunoblot analysis demonstrated strong CHAF1B upregulation between 2 and 4 days post-infection (Fig. 4B), at which point newly infected cells begin to rapidly proliferate as they transition from the EBV pre-latency program to latency IIb (12, 37). Published LCL Chip-seq data (38–41) showed Epstein-Barr nuclear antigens 2, LP, 3A, 3C and LMP1-activated NF-kB subunit occupancy at or near the CHAF1A, CHAF1B and RBBP4 promoters (Fig.…”

Section: Resultsmentioning

confidence: 99%

Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation

Zhang

Jiang

Trudeau

et al. 2020

Preprint

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19Epstein-Barr virus (EBV) infects 95% of adults worldwide and causes infectious mononucleosis. 20 EBV is associated with endemic Burkitt lymphoma, Hodgkin lymphoma, post-transplant 21 lymphomas, nasopharyngeal and gastric carcinomas. In these cancers and in most infected B-cells, 22 Suggestive of an early role in establishment of latency, EBV strongly upregulated CAF1 32 expression in newly infected primary human B-cells prior to the first mitosis, and histone 3.1 and 33 3.3 were loaded on the EBV genome by this timepoint. Knockout of CAF1 subunit CHAF1B 34 impaired establishment of latency in newly EBV-infected Burkitt cells. A non-redundant latency 35 maintenance role was also identified for the DNA synthesis-independent histone 3.3 loader HIRA. 36Since EBV latency also requires histone chaperones ATRX and DAXX, EBV coopts multiple host 37 histone pathways to maintain latency, and these are potential targets for lytic induction therapeutic 38 approaches. 39 40 IMPORTANCE 41Epstein-Barr virus (EBV) was discovered as the first human tumor virus in endemic Burkitt 42 lymphoma, the most common childhood cancer in sub-Saharan Africa. In Burkitt lymphoma and 43 in 200,000 EBV-associated cancers per year, epigenetic mechanisms maintain viral latency, where 44 lytic cycle factors are silenced. This property complicated EBV's discovery and facilitates tumor 45 immunoevasion. DNA methylation and chromatin-based mechanisms contribute to lytic gene 46 silencing. Here, we identify histone chaperones CAF1 and HIRA, which have key roles in host 47 DNA replication-dependent and replication independent pathways, respectively, are each 48 important for EBV latency. EBV strongly upregulates CAF1 in newly infected B-cells, where viral 49 genomes acquire histone 3.1 and 3.3 variants prior to the first mitosis. Since histone chaperones 50 ATRX and DAXX also function in maintenance of EBV latency, our results suggest that EBV 51 coopts multiple histone pathways to reprogram viral genomes and highlights targets for lytic 52 induction therapeutic strategies. 53 54The gamma-herpesvirus Epstein-Barr virus (EBV) persistently infects nearly 95% of adults 59 worldwide (1). EBV is the etiological agent of infectious mononucleosis and is also causally-60 associated with multiple human cancers, including endemic Burkitt lymphoma (eBL), Hodgkin 61 lymphoma, post-transplant lymphoproliferative disease, HIV-associated lymphomas, 62 nasopharyngeal carcinoma and gastric carcinoma (2). Tumor cells contain multiple copies of 63 chromatinized, non-integrated, double-stranded DNA EBV genomes, where incompletely defined 64 epigenetic pathways maintain a state of viral latency and in which most cells do not produce 65 infectious virus. 66 EBV initiates lifelong infection by translocating across the tonsillar epithelium to colonize the 67 B-cell compartment (3, 4). Virion deliver unchromatinized, encapsidated, linear EBV genomes to 68 newly infected cells, which traffic to the nucleus. Upon nuclear entry, incoming genomes are 69 circularized by host D...

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“…In B cells, the transcription of LMP1 is regulated by EBNA2 (40). Prior work indicates that EBNA2-regulated genes, including c-Myc and CD23, are induced to higher levels at day 7 post infection than in LCLs suggesting that EBNA2 activity is not broadly suppressed during early infection (32). However, it remained a possibility that LMP1 expression was low during early infection because of poor EBNA2 recruitment to the bi-directional LMP1/2B promoter.…”

Section: Resultsmentioning

confidence: 99%

“…Despite EBNA2 recruitment to the LMP1 promoter, reduced H3K9 acetylation suggested poor LMP1 transcription. Early after infection when LMP1 expression is lowest, c-Myc is strongly activated by EBNA2, and during the time frame that LMP1 expression increases the expression of c-Myc and its targets are subsequently attenuated (32). Given this correlation, we sought to test the role of c-Myc in the regulation of LMP1 expression.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, EBV induces c-Myc expression upon infection of B cells by utilizing EBNA2 to co-opt native super-enhancer architecture upstream of c-Myc (31). Upon de novo infection, c-Myc levels peak within the first week after infection, then wane, but remain elevated throughout LCL outgrowth where c-Myc is crucial for the maintenance of the LCL phenotype (32, 33). This conflicts with the NFκB addiction observed in LCLs, as the c-Myc and NFκB signaling pathways have been shown to be directly incompatible (34).…”

Section: Introductionmentioning

confidence: 99%

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c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

Price

Messinger

Luftig

2017

Preprint

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13Recent evidence has shown that the EBV oncogene LMP1 is not expressed at high levels 14 early after EBV-infection of primary B cells, despite its being essential for the long-term outgrowth 15 of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 16 increased fifty-fold between seven days post infection and the LCL state. Metabolic labeling of 17 nascently transcribed mRNA indicated this was primarily a transcription-mediated event. EBNA2, 18the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, 19were recruited to the LMP1 locus similarly early and late after infection. However, the activating 20 histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to early-infected B 21 cells. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression 22

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An ATM/Chk2-mediated DNA damage responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells

Cited by 29 publications

References 0 publications

Senescent cells: Living or dying is a matter of NK cells

Senescent cells: Living or dying is a matter of NK cells

Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation

c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

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