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Article ; Online: P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway.

Wang, Zhijia / Mačáková, Monika / Bugai, Andrii / Kuznetsov, Sergey G / Hassinen, Antti / Lenasi, Tina / Potdar, Swapnil / Friedel, Caroline C / Barborič, Matjaž

Nucleic acids research

2023 Volume 51, Issue 4, Page(s) 1687–1706

Abstract: Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting ... ...

Abstract	Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.
MeSH term(s)	Apoptosis ; Cell Line, Tumor ; Cell Survival ; Phosphatidylinositol 3-Kinases/metabolism ; Positive Transcriptional Elongation Factor B/antagonists & inhibitors ; Positive Transcriptional Elongation Factor B/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Tumor Suppressor Protein p53/genetics ; Humans
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27)
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad001
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Zs.A 1067: Show issues

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Article ; Online: Mutual relationships between transcription and pre-mRNA processing in the synthesis of mRNA.

Lenasi, Tina / Barboric, Matjaz

Wiley interdisciplinary reviews. RNA

2013 Volume 4, Issue 2, Page(s) 139–154

Abstract: The generation of messenger RNA (mRNA) in eukaryotes is achieved by transcription from the DNA template and pre-mRNA processing reactions of capping, splicing, and polyadenylation. Although RNA polymerase II (RNAPII) catalyzes the synthesis of pre-mRNA, ... ...

Abstract	The generation of messenger RNA (mRNA) in eukaryotes is achieved by transcription from the DNA template and pre-mRNA processing reactions of capping, splicing, and polyadenylation. Although RNA polymerase II (RNAPII) catalyzes the synthesis of pre-mRNA, it also serves as a principal coordinator of the processing reactions in the course of transcription. In this review, we focus on the interplay between transcription and cotranscriptional pre-mRNA maturation events, mediated by the recruitment of RNA processing factors to differentially phosphorylated C-terminal domain of Rbp1, the largest subunit of RNAPII. Furthermore, we highlight the bidirectional nature of the interplay by discussing the impact of RNAPII kinetics on pre-mRNA processing as well as how the processing events reach back to different phases of gene transcription.
MeSH term(s)	Animals ; Humans ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA Processing, Post-Transcriptional ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Transcription, Genetic
Chemical Substances	RNA Precursors ; RNA, Messenger
Language	English
Publishing date	2013-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2634714-3
ISSN	1757-7012 ; 1757-7004
ISSN (online)	1757-7012
ISSN	1757-7004
DOI	10.1002/wrna.1148
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Zs.A 6953: Show issues

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Article ; Online: P-TEFb stimulates transcription elongation and pre-mRNA splicing through multilateral mechanisms.

Lenasi, Tina / Barboric, Matjaz

RNA biology

2010 Volume 7, Issue 2, Page(s) 145–150

Abstract: Promoter-proximal pausing of RNA polymerase II (RNAPII) across the genome has renewed our attention to the early transcriptional events that control the establishment of pausing and the release of RNAPII into a productive transcription elongation. Here, ... ...

Abstract	Promoter-proximal pausing of RNA polymerase II (RNAPII) across the genome has renewed our attention to the early transcriptional events that control the establishment of pausing and the release of RNAPII into a productive transcription elongation. Here, we review our current understanding of the transcriptional cycle by RNAPII with a particular emphasis on the mechanisms that stimulate transcription elongation and cotranscriptional pre-mRNA splicing through an essential transcriptional kinase, the positive transcription elongation factor b (P-TEFb). We illustrate that by targeting a limited set of transcription elongation factors and paused RNAPII molecule during a promoter-proximal phase of transcription, P-TEFb unleashes an extensive crosstalk between transcription apparatus, RNA processing factors and chromatin for optimal production of mRNA.
MeSH term(s)	Animals ; Positive Transcriptional Elongation Factor B/metabolism ; RNA Polymerase II/chemistry ; RNA Polymerase II/metabolism ; RNA Precursors/genetics ; RNA Splicing/genetics ; Ribonucleoproteins, Small Nuclear/metabolism ; Transcription, Genetic
Chemical Substances	RNA Precursors ; Ribonucleoproteins, Small Nuclear ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2010-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1555-8584
ISSN (online)	1555-8584
DOI	10.4161/rna.7.2.11057
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Article ; Online: Kick-sTARting HIV-1 transcription elongation by 7SK snRNP deporTATion.

Barboric, Matjaz / Lenasi, Tina

Nature structural & molecular biology

2010 Volume 17, Issue 8, Page(s) 928–930

Abstract: The HIV-1 Tat protein promotes viral transcription elongation by recruiting P-TEFb to RNA element TAR on the viral mRNA. Recent work from D'Orso and Frankel uncovers unexpected aspects of this process. ...

Abstract	The HIV-1 Tat protein promotes viral transcription elongation by recruiting P-TEFb to RNA element TAR on the viral mRNA. Recent work from D'Orso and Frankel uncovers unexpected aspects of this process.
MeSH term(s)	Gene Expression Regulation, Viral ; HIV Long Terminal Repeat/genetics ; HIV-1/genetics ; Models, Genetic ; Positive Transcriptional Elongation Factor B/metabolism ; RNA Polymerase II/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; Transcription, Genetic ; Transcriptional Activation/genetics ; tat Gene Products, Human Immunodeficiency Virus/genetics ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Ribonucleoproteins, Small Nuclear ; tat Gene Products, Human Immunodeficiency Virus ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2010-08-04
Publishing country	United States
Document type	Comment ; News
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb0810-928
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Zs.A 4101: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 56: Show issues

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Article: P-TEFb stimulates transcription elongation and pre-mRNA splicing through multilateral mechanisms

Lenasi, Tina / Barboric, Matjaz

RNA biology. 2010 Mar. 1, v. 7, no. 2

2010

Abstract	Promoter-proximal pausing of RNA polymerase II (RNAPII) across the genome has renewed our attention to the early transcriptional events that control the establishment of pausing and the release of RNAPII into a productive transcription elongation. Here, we review our current understanding of the transcriptional cycle by RNAPII with a particular emphasis on the mechanisms that stimulate transcription elongation and cotranscriptional pre-mRNA splicing through an essential transcriptional kinase, the positive transcription elongation factor b (P-TEFb). We illustrate that by targeting a limited set of transcription elongation factors and paused RNAPII molecule during an early phase of transcription, P-TEFb unleashes an extensive crosstalk between transcription apparatus, RNA processing factors and chromatin for optimal production of mRNA.
Keywords	DNA-directed RNA polymerase ; chromatin ; genome ; transcription (genetics) ; transcriptional elongation factors
Language	English
Dates of publication	2010-0301
Size	p. 145-150.
Publishing place	Taylor & Francis
Document type	Article
ISSN	1555-8584
DOI	10.4161/rna.7.2.11057
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Article ; Online: Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (P-TEFb).

Lenasi, Tina / Peterlin, B Matija / Barboric, Matjaz

The Journal of biological chemistry

2011 Volume 286, Issue 26, Page(s) 22758–22768

Abstract: Promoter-proximal pausing of RNAPII coincides with the formation of the cap structure at the 5' end of pre-mRNA, which is bound by the cap-binding protein complex (CBC). Although the positive transcription elongation factor b (P-TEFb) stimulates the ... ...

Abstract	Promoter-proximal pausing of RNAPII coincides with the formation of the cap structure at the 5' end of pre-mRNA, which is bound by the cap-binding protein complex (CBC). Although the positive transcription elongation factor b (P-TEFb) stimulates the release of RNAPII from pausing and promotes transcription elongation and alternative splicing by phosphorylating the RNAPII C-terminal domain at Ser2 (S2-P RNAPII), it is unknown whether CBC facilitates these events. In this study, we report that CBC interacts with P-TEFb and transcriptionally engaged RNAPII and is globally required for optimal levels of S2-P RNAPII. Quantitative nascent RNA immunoprecipitation and ChIP experiments reveal that depletion of CBC attenuates HIV-1 Tat transactivation and impedes transcription elongation of investigated CBC-dependent endogenous genes by decreasing the levels of P-TEFb and S2-P RNAPII, leading to accumulation of RNAPII in the body of these genes. Finally, CBC is essential for the promotion of alternative splicing through facilitating P-TEFb, S2-P RNAPII, and splicing factor 2/alternative splicing factor occupancy at a splicing minigene. These findings disclose a vital role of CBC in connecting pre-mRNA capping to transcription elongation and alternative splicing via P-TEFb.
MeSH term(s)	Alternative Splicing/physiology ; HeLa Cells ; Humans ; Positive Transcriptional Elongation Factor B/genetics ; Positive Transcriptional Elongation Factor B/metabolism ; RNA Cap-Binding Proteins/genetics ; RNA Cap-Binding Proteins/metabolism ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; RNA Precursors/biosynthesis ; RNA Precursors/genetics ; Transcription, Genetic/physiology
Chemical Substances	RNA Cap-Binding Proteins ; RNA Precursors ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2011-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.235077
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Uc I Zs.108: Show issues

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Article ; Online: P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress.

Bugai, Andrii / Quaresma, Alexandre J C / Friedel, Caroline C / Lenasi, Tina / Düster, Robert / Sibley, Christopher R / Fujinaga, Koh / Kukanja, Petra / Hennig, Thomas / Blasius, Melanie / Geyer, Matthias / Ule, Jernej / Dölken, Lars / Barborič, Matjaž

Molecular cell

2019 Volume 74, Issue 2, Page(s) 254–267.e10

Abstract: DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription ...

Abstract	DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). This is mediated by activation of p38
MeSH term(s)	Apoptosis/genetics ; Cell Survival/genetics ; DNA Damage/genetics ; HEK293 Cells ; Humans ; Positive Transcriptional Elongation Factor B/genetics ; RNA Polymerase II/genetics ; RNA, Long Noncoding/genetics ; RNA-Binding Proteins/genetics ; Ribonucleoproteins, Small Nuclear/genetics ; Transcription, Genetic ; p38 Mitogen-Activated Protein Kinases/genetics
Chemical Substances	RBM7 protein, human ; RNA, Long Noncoding ; RNA-Binding Proteins ; Ribonucleoproteins, Small Nuclear ; long non-coding RNA 7SK, human ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2019-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2019.01.033
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Zs.A 5055: Show issues

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Article: HIV latency: present knowledge, future directions.

Contreras, Xavier / Lenasi, Tina / Peterlin, B Matija

Future virology

2009 Volume 1, Issue 6, Page(s) 733–745

Abstract: Current therapies do not eradicate HIV from infected patients. Indeed, HIV hides in a latent form insensitive to these therapies. Thus, one priority is to purge these latent reservoirs. But what mechanisms are responsible for latency and what are the ... ...

Abstract	Current therapies do not eradicate HIV from infected patients. Indeed, HIV hides in a latent form insensitive to these therapies. Thus, one priority is to purge these latent reservoirs. But what mechanisms are responsible for latency and what are the reservoirs of latently infected cells? The present knowledge in terms of HIV latency is still incomplete and current therapeutic strategies fail to eradicate completely latently infected cells. What could the future bring?
Language	English
Publishing date	2009-05-18
Publishing country	England
Document type	Journal Article
ISSN	1746-0794
ISSN	1746-0794
DOI	10.2217/17460794.1.6.733
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Article ; Online: Transcriptional interference antagonizes proviral gene expression to promote HIV latency.

Lenasi, Tina / Contreras, Xavier / Peterlin, B Matija

Cell host & microbe

2008 Volume 4, Issue 2, Page(s) 123–133

Abstract: Eradication of the latent HIV reservoir remains a major barrier to curing AIDS. However, the mechanisms that direct viral persistence in the host are not well understood. Studying a model system of postintegration latency, we found that viral integration ...

Abstract	Eradication of the latent HIV reservoir remains a major barrier to curing AIDS. However, the mechanisms that direct viral persistence in the host are not well understood. Studying a model system of postintegration latency, we found that viral integration into the actively transcribed host genes led to transcriptional interference (TI) caused by the elongating RNA polymerase II (RNAPII) transcribing through the viral promoter. The resulting physical exclusion of preinitiation complex formation on the 5' long terminal repeat (LTR) promoted the silencing of HIV transcription. This block could be counteracted by inhibiting the upstream transcription or cooperatively activating viral transcription initiation and elongation. Importantly, PCR-based analysis, which detects host transcription through the 5'LTR independently of the viral integration site, revealed substantial levels of this transcription in HIV-infected primary CD4(+) T cells. Collectively, our findings suggest that TI contributes significantly to HIV latency and should be considered when attempting to purge the latent reservoir.
MeSH term(s)	CD4-Positive T-Lymphocytes/virology ; Gene Expression Regulation, Viral ; Genome, Viral ; Glycoproteins/genetics ; Glycoproteins/metabolism ; HIV/genetics ; HIV/physiology ; HIV Infections/genetics ; HIV Infections/virology ; HIV Long Terminal Repeat ; Host-Pathogen Interactions ; Humans ; Jurkat Cells ; Proviruses/genetics ; Proviruses/physiology ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Transcription, Genetic ; Virus Latency
Chemical Substances	Glycoproteins ; tissue-factor-pathway inhibitor 2 ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2008-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2008.05.016
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Zs.A 6578: Show issues

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Article: Distal regulation of alternative splicing by splicing enhancer in equine beta-casein intron 1.

Lenasi, Tina / Peterlin, B Matija / Dovc, Peter

RNA (New York, N.Y.)

2006 Volume 12, Issue 3, Page(s) 498–507

Abstract: The complexity of cotranscriptional splicing is reflected in the coordinated interplay between various cis-elements and transacting factors. In this report, we demonstrated that a cis-element in intron 1 of the equine beta-casein gene (intronic splicing ... ...

Abstract	The complexity of cotranscriptional splicing is reflected in the coordinated interplay between various cis-elements and transacting factors. In this report, we demonstrated that a cis-element in intron 1 of the equine beta-casein gene (intronic splicing enhancer 1, ISE1) increases the inclusion of all weak exons in its pre-mRNA. The ISE1 also functioned on a hybrid transcript, which was transcribed from the alpha-globin promoter, where it increased the inclusion of the human fibronectin EDA exon and the beta-casein exon 5. The region of ISE1 necessary for its function included the same sequence as is found in some exonic splicing enhancers. Since the ISE1 influenced the splicing of the entire transcript from intron 1, we propose a model for the cotranscriptional splicing of beta-casein mRNA, where the 5' end of the growing transcript remains associated with the C-terminal domain of RNA polymerase II. Thus, the ISE1 remains in close proximity to the mRNA exit groove throughout transcription and influences all weak exons as soon as they are copied.
MeSH term(s)	Alternative Splicing ; Animals ; Base Sequence ; Caseins/genetics ; DNA/genetics ; Enhancer Elements, Genetic ; Exons ; Female ; Globins/genetics ; Horses/genetics ; Horses/metabolism ; Humans ; Introns ; Molecular Sequence Data ; Mutagenesis ; Polymorphism, Genetic ; RNA Precursors/genetics ; RNA Precursors/metabolism
Chemical Substances	Caseins ; RNA Precursors ; Globins (9004-22-2) ; DNA (9007-49-2)
Language	English
Publishing date	2006-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1355-8382
ISSN	1355-8382
DOI	10.1261/rna.7261206
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Zs.A 4777: Show issues

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