Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection
T cells play a critical role in controlling viral infection; however, the mechanisms regulating their responses remain incompletely understood. Here, we investigated the role of topoisomerase IIA (Top2α, an enzyme that is essential in resolving entangled DNA strands during replication) in telomeric DNA damage and T cell dysfunction during viral infection. We demonstrated that T cells derived from patients with chronic viral (HBV, HCV, and HIV) infection had lower Top2α protein levels and enzymatic activity, along with an accumulation of the Top2α cleavage complex (Top2cc) in genomic DNA. In addition, T cells from virally infected subjects with lower Top2α levels were vulnerable to Top2α inhibitor-induced cell apoptosis, indicating an important role for Top2α in preventing DNA topological disruption and cell death. Using Top2α inhibitor (ICRF193 or Etoposide)-treated primary T cells as a model, we demonstrated that disrupting the DNA topology promoted DNA damage and T cell apoptosis via Top2cc accumulation that is associated with protein-DNA breaks (PDB) at genomic DNA. Disruption of the DNA topology was likely due to diminished expression of tyrosyl-DNA phosphodiesterase 2 (TDP2), which was inhibited in T cells in vitro by Top2α inhibitor and in vivo by chronic viral infection. These results suggest that immune-evasive viruses (HBV, HCV, and HIV) can disrupt T cell DNA topology as a mechanism of dysregulating host immunity and establishing chronic infection. Thus, restoring the DNA topologic machinery may serve as a novel strategy to protect T cells from unwanted DNA damage and to maintain immune competence.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
Cell death & disease - 11(2020), 3 vom: 19. März, Seite 196 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Dang, Xindi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.04.2021 Date Revised 23.04.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41419-020-2395-2 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM30779783X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM30779783X | ||
| 003 | DE-627 | ||
| 005 | 20240423231846.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41419-020-2395-2 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1384.xml |
| 035 | |a (DE-627)NLM30779783X | ||
| 035 | |a (NLM)32193368 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Dang, Xindi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 13.04.2021 | ||
| 500 | |a Date Revised 23.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a T cells play a critical role in controlling viral infection; however, the mechanisms regulating their responses remain incompletely understood. Here, we investigated the role of topoisomerase IIA (Top2α, an enzyme that is essential in resolving entangled DNA strands during replication) in telomeric DNA damage and T cell dysfunction during viral infection. We demonstrated that T cells derived from patients with chronic viral (HBV, HCV, and HIV) infection had lower Top2α protein levels and enzymatic activity, along with an accumulation of the Top2α cleavage complex (Top2cc) in genomic DNA. In addition, T cells from virally infected subjects with lower Top2α levels were vulnerable to Top2α inhibitor-induced cell apoptosis, indicating an important role for Top2α in preventing DNA topological disruption and cell death. Using Top2α inhibitor (ICRF193 or Etoposide)-treated primary T cells as a model, we demonstrated that disrupting the DNA topology promoted DNA damage and T cell apoptosis via Top2cc accumulation that is associated with protein-DNA breaks (PDB) at genomic DNA. Disruption of the DNA topology was likely due to diminished expression of tyrosyl-DNA phosphodiesterase 2 (TDP2), which was inhibited in T cells in vitro by Top2α inhibitor and in vivo by chronic viral infection. These results suggest that immune-evasive viruses (HBV, HCV, and HIV) can disrupt T cell DNA topology as a mechanism of dysregulating host immunity and establishing chronic infection. Thus, restoring the DNA topologic machinery may serve as a novel strategy to protect T cells from unwanted DNA damage and to maintain immune competence | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Diketopiperazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a TERF2 protein, human |2 NLM | |
| 650 | 7 | |a Telomeric Repeat Binding Protein 2 |2 NLM | |
| 650 | 7 | |a Topoisomerase II Inhibitors |2 NLM | |
| 650 | 7 | |a 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione |2 NLM | |
| 650 | 7 | |a 21416-68-2 |2 NLM | |
| 650 | 7 | |a Etoposide |2 NLM | |
| 650 | 7 | |a 6PLQ3CP4P3 |2 NLM | |
| 650 | 7 | |a PARP1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.4.2.30 |2 NLM | |
| 650 | 7 | |a Poly (ADP-Ribose) Polymerase-1 |2 NLM | |
| 650 | 7 | |a EC 2.4.2.30 |2 NLM | |
| 650 | 7 | |a Telomerase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.49 |2 NLM | |
| 650 | 7 | |a Phosphoric Diester Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.1.4.- |2 NLM | |
| 650 | 7 | |a TDP2 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.4.- |2 NLM | |
| 650 | 7 | |a DNA Topoisomerases, Type II |2 NLM | |
| 650 | 7 | |a EC 5.99.1.3 |2 NLM | |
| 700 | 1 | |a Ogbu, Stella C |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Lam Ngoc Thao |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Dechao |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Lam Nhat |e verfasserin |4 aut | |
| 700 | 1 | |a Khanal, Sushant |e verfasserin |4 aut | |
| 700 | 1 | |a Schank, Madison |e verfasserin |4 aut | |
| 700 | 1 | |a Thakuri, Bal Krishna Chand |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiao Y |e verfasserin |4 aut | |
| 700 | 1 | |a Morrison, Zheng D |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhengke |e verfasserin |4 aut | |
| 700 | 1 | |a El Gazzar, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Shunbin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhengqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Jonathan P |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Zhi Q |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell death & disease |d 2010 |g 11(2020), 3 vom: 19. März, Seite 196 |w (DE-627)NLM202030881 |x 2041-4889 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2020 |g number:3 |g day:19 |g month:03 |g pages:196 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41419-020-2395-2 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2020 |e 3 |b 19 |c 03 |h 196 | ||