DNA dependent protein kinase (DNA-PK) enhances HIV transcription by promoting RNA polymerase II activity and recruitment of transcription machinery at HIV LTR

Zicari, Sonia; Sharma, Adhikarimayum Lakhikumar; Sahu, Geetaram; Dubrovsky, Larisa; Sun, Lin; Yue, Han; Jada, Tejaswi; Ochem, Alex; Simon, Gary L.; Bukrinsky, Michael; Tyagi, Mudit

doi:10.18632/oncotarget.27487

Cited by 18 publications

(18 citation statements)

References 81 publications

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“…Initially, Tyagi et al [ 39 ] demonstrated a functional interaction between DNA-dependent protein kinase (DNA-PK) and RNAP II during HIV transcription, such that the knockdown of endogenous DNA-PK using small hairpin RNAs resulted in a significant reduction in HIV transcription. Recently, the Tyagi lab [ 40 ] specifically showed that DNA-PK, besides catalyzing RNAP II CTD phosphorylation, also enhances the recruitment of P-TEFb to the HIV LTR. Thus, DNA-PK concomitantly increases the phosphorylation of the CTD of RNAP II at Serine 5 and Serine 2, thereby stimulating both HIV transcriptional initiation and elongation.…”

Section: Non-epigenetic Regulation and Reactivation Of Hiv Latencymentioning

confidence: 99%

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency

Hokello

Sharma

Tyagi

2021

IJMS

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The persistence of latent HIV provirus pools in different resting CD4+ cell subsets remains the greatest obstacle in the current efforts to treat and cure HIV infection. Recent efforts to purge out latently infected memory CD4+ T-cells using latency-reversing agents have failed in clinical trials. This review discusses the epigenetic and non-epigenetic mechanisms of HIV latency control, major limitations of the current approaches of using latency-reversing agents to reactivate HIV latency in resting CD4+ T-cells, and potential solutions to these limitations.

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Section: Non-epigenetic Regulation and Reactivation Of Hiv Latencymentioning

confidence: 99%

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency

Hokello

Sharma

Tyagi

2021

IJMS

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“…Finally, it has recently been shown that, in different cell lines, DNA-PK increases the phosphorylation of RNAP II C-terminal domain at S5 and S2 by directly catalyzing phosphorylation and by augmenting the recruitment of P-TEFb at HIV LTR. Thus, the DNA-PK-dependent phosphorylation of RNAP II likely plays an important role in both transcription initiation and elongation [ 14 ]. Considering the role of Top II and DNA-PKcs in pause release of RNAP II through the DSB formation in cellular stimuli induced genes, one may assume that LTR-driven transcription may also be regulated in the same manner.…”

Section: Dna-pk Targets In Hiv Replicationmentioning

confidence: 99%

“…Although this idea is more speculative and needs further testing, TRIM28, which is main maintainer of paused RNAP II, has been demonstrated to participate in HIV latency by SUMOylating CDK9 and inhibiting P-TEFb [ 149 ]. Moreover, DNA-PK utilizes the mechanism of the TRIM28 recruitment at LTR and its phosphorylation to release paused RNAP II, thus influencing different steps of transcription from the LTR promoter [ 14 ].…”

Section: Dna-pk Targets In Hiv Replicationmentioning

confidence: 99%

“…For example, phosphorylation of TRIM28 by DNA-PK converts it to an elongation factor during transcription regulation [ 13 ]. Just recently, the necessity of RNA polymerase II phosphorylation by DNA-PK for the efficient transcription from the HIV-1 promoter and reactivation of the latent provirus has been clearly demonstrated [ 14 ]. However, the mechanism of DNA-PK activation during transcription remains obscure, since the DNA-binding component of DNA-PK, the Ku protein, has high affinity to DNA ends, whereas its ability to interact with internal DNA sequences is not proved clearly [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation Targets of DNA-PK and Their Role in HIV-1 Replication

Anisenko

Kan

Shadrina

et al. 2020

Cells

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The DNA dependent protein kinase (DNA-PK) is a trimeric nuclear complex consisting of a large protein kinase and the Ku heterodimer. The kinase activity of DNA-PK is required for efficient repair of DNA double-strand breaks (DSB) by non-homologous end joining (NHEJ). We also showed that the kinase activity of DNA-PK is essential for post-integrational DNA repair in the case of HIV-1 infection. Besides, DNA-PK is known to participate in such cellular processes as protection of mammalian telomeres, transcription, and some others where the need for its phosphorylating activity is not clearly elucidated. We carried out a systematic search and analysis of DNA-PK targets described in the literature and identified 67 unique DNA-PK targets phosphorylated in response to various in vitro and/or in vivo stimuli. A functional enrichment analysis of DNA-PK targets and determination of protein–protein associations among them were performed. For 27 proteins from these 67 DNA-PK targets, their participation in the HIV-1 life cycle was demonstrated. This information may be useful for studying the functioning of DNA-PK in various cellular processes, as well as in various stages of HIV-1 replication.

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“…However, Kim and colleagues demonstrated that following activation of the TCR, P‐TEFb, which is a cellular co‐factor for viral Tat protein, is mobilized through an ERK‐dependent pathway to enhance HIV transcriptional elongation before new Tat synthesis [29]. To further extend, besides ERK‐dependent pathways, we have shown the crucial role of DNA‐PK in facilitating both the initiation and elongation phases of HIV transcription [30–32]. Other cellular factors such as the phosphorylated‐Spt5 subunit of the 5, 6‐dichloro‐1‐b‐D‐ribo‐furanosylbenzimidazole (DRB) sensitivity inducing factor (DSIF) stabilize the elongating transcription complexes by preventing premature RNAP II disengagement from DNA templates [6,26].…”

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confidence: 99%

AP‐1 and NF‐κB synergize to transcriptionally activate latent HIV upon T‐cell receptor activation

2021

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Latent HIV‐1 proviruses are capable of reactivating productive lytic infection, but the precise molecular mechanisms underlying emergence from latency are poorly understood. In this study, we determined the contribution of the transcription factors NF‐κB, NFAT, and AP‐1 in the reactivation of latent HIV following T‐cell receptor (TCR) activation using Jurkat T‐cell clones harboring single latent HIV proviruses. Our findings demonstrate that during reactivation from latency, NF‐κB enhances HIV transcription while NFAT inhibits it by competing with NF‐κB for overlapping binding sites on the HIV long terminal repeat (LTR). We have also demonstrated for the first time the molecular contribution of AP‐1 in the reactivation of HIV from latency, whereby AP‐1 synergizes with NF‐κB to regulate HIV transcriptional elongation following TCR activation.

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DNA dependent protein kinase (DNA-PK) enhances HIV transcription by promoting RNA polymerase II activity and recruitment of transcription machinery at HIV LTR

Cited by 18 publications

References 81 publications

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency

Combinatorial Use of Both Epigenetic and Non-Epigenetic Mechanisms to Efficiently Reactivate HIV Latency

Phosphorylation Targets of DNA-PK and Their Role in HIV-1 Replication

AP‐1 and NF‐κB synergize to transcriptionally activate latent HIV upon T‐cell receptor activation

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