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Article ; Online: The Interlocking Lives of LARP7: Fine-Tuning Transcription, RNA Modification, and Splicing through Multiple Non-coding RNAs.

Frilander, Mikko J / Barborič, Matjaž

2020 Volume 78, Issue 1, Page(s) 5–8

Abstract: Elegant studies by Hasler et al. (2020) and Wang et al. (2020) uncover a novel role of LARP7 in facilitating the 2'-O-methylation of the spliceosomal U6 snRNA, which is functionally required for fidelity of pre-mRNA splicing and development of male germ ... ...

Abstract	Elegant studies by Hasler et al. (2020) and Wang et al. (2020) uncover a novel role of LARP7 in facilitating the 2'-O-methylation of the spliceosomal U6 snRNA, which is functionally required for fidelity of pre-mRNA splicing and development of male germ cells.
MeSH term(s)	Animals ; Base Sequence ; Male ; Mice ; Nucleic Acid Conformation ; RNA Splicing ; RNA, Small Nuclear ; Spermatogenesis
Chemical Substances	RNA, Small Nuclear ; U6 small nuclear RNA
Language	English
Publishing date	2020-04-03
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.03.015
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Zs.A 5055: Show issues

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Article ; Online: Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release.

Wang, Zhijia / Himanen, Samu V / Haikala, Heidi M / Friedel, Caroline C / Vihervaara, Anniina / Barborič, Matjaž

Nucleic acids research

2023 Volume 51, Issue 20, Page(s) 10970–10991

Abstract: P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding of their interplay could inform the design of novel anti-cancer strategies. While down-regulation ... ...

Abstract	P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding of their interplay could inform the design of novel anti-cancer strategies. While down-regulation of DNA repair genes in CDK12-targeted cancer cells is being explored therapeutically, little is known about mechanisms and significance of transcriptional induction upon inhibition of CDK12. We show that selective targeting of CDK12 in colon cancer-derived cells activates P-TEFb via its release from the inhibitory 7SK snRNP. In turn, P-TEFb stimulates Pol II pause release at thousands of genes, most of which become newly dependent on P-TEFb. Amongst the induced genes are those stimulated by hallmark pathways in cancer, including p53 and NF-κB. Consequently, CDK12-inhibited cancer cells exhibit hypersensitivity to inhibitors of P-TEFb. While blocking P-TEFb triggers their apoptosis in a p53-dependent manner, it impedes cell proliferation irrespective of p53 by preventing induction of genes downstream of the DNA damage-induced NF-κB signaling. In summary, stimulation of Pol II pause release at the signal-responsive genes underlies the functional dependence of CDK12-inhibited cancer cells on P-TEFb. Our study establishes the mechanistic underpinning for combinatorial targeting of CDK12 with either P-TEFb or the induced oncogenic pathways in cancer.
MeSH term(s)	Neoplasms/genetics ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Positive Transcriptional Elongation Factor B/genetics ; Positive Transcriptional Elongation Factor B/metabolism ; Ribonucleoproteins, Small Nuclear/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; RNA-Binding Proteins/metabolism ; Tumor Suppressor Protein p53/genetics ; Humans ; Cell Line, Tumor
Chemical Substances	NF-kappa B ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; Ribonucleoproteins, Small Nuclear ; RNA Polymerase II (EC 2.7.7.-) ; RNA-Binding Proteins ; Tumor Suppressor Protein p53
Language	English
Publishing date	2023-10-09
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/gkad792
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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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Article ; Online: The two sides of Tat.

Barboric, Matjaz / Fujinaga, Koh

eLife

2016 Volume 5, Page(s) e12686

Abstract: A virus protein called Tat plays a dual role in HIV infection by regulating the expression of genes belonging to the virus and genes belonging to the host cells. ...

Abstract	A virus protein called Tat plays a dual role in HIV infection by regulating the expression of genes belonging to the virus and genes belonging to the host cells.
MeSH term(s)	HIV/physiology ; HIV Infections/virology ; Host-Pathogen Interactions ; Humans ; Transcription, Genetic ; Virus Replication ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	tat Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2016-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.12686
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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: Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb.

C Quaresma, Alexandre J / Bugai, Andrii / Barboric, Matjaz

Nucleic acids research

2016 Volume 44, Issue 16, Page(s) 7527–7539

Abstract: Release of RNA polymerase II (Pol II) from promoter-proximal pausing has emerged as a critical step regulating gene expression in multicellular organisms. The transition of Pol II into productive elongation requires the kinase activity of positive ... ...

Abstract	Release of RNA polymerase II (Pol II) from promoter-proximal pausing has emerged as a critical step regulating gene expression in multicellular organisms. The transition of Pol II into productive elongation requires the kinase activity of positive transcription elongation factor b (P-TEFb), which is itself under a stringent control by the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP) complex. Here, we provide an overview on stimulating Pol II pause release by P-TEFb and on sequestering P-TEFb into 7SK snRNP. Furthermore, we highlight mechanisms that govern anchoring of 7SK snRNP to chromatin as well as means that release P-TEFb from the inhibitory complex, and propose a unifying model of P-TEFb activation on chromatin. Collectively, these studies shine a spotlight on the central role of RNA binding proteins (RBPs) in directing the inhibition and activation of P-TEFb, providing a compelling paradigm for controlling Pol II transcription with a non-coding RNA.
MeSH term(s)	Animals ; Chromatin/metabolism ; Humans ; Models, Biological ; Positive Transcriptional Elongation Factor B/metabolism ; RNA Polymerase II/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; Transcription Elongation, Genetic
Chemical Substances	Chromatin ; Ribonucleoproteins, Small Nuclear ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2016-09-19
Publishing country	England
Document type	Journal Article ; Review
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/gkw585
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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)
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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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