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Article: Kevin Struhl. Interview.

Struhl, Kevin

2007 Volume 18, Issue 1, Page(s) R7–9

MeSH term(s)	Gene Expression Regulation ; Genetics ; United States
Language	English
Publishing date	2007-07-11
Publishing country	England
Document type	Interview
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2007.10.060
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Article ; Online: Intrinsically disordered regions (IDRs): A vague and confusing concept for protein function.

Struhl, Kevin

Molecular cell

2024 Volume 84, Issue 7, Page(s) 1186–1187

Abstract: The term "intrinsically disordered region" (IDR) in proteins has been used in numerous publications. However, most proteins contain IDRs, the term refers to very different types of structures and functions, and many IDRs become structured upon ... ...

Abstract	The term "intrinsically disordered region" (IDR) in proteins has been used in numerous publications. However, most proteins contain IDRs, the term refers to very different types of structures and functions, and many IDRs become structured upon interaction with other biomolecules. Thus, IDR is an unnecessary, vague, and ultimately confusing concept.
MeSH term(s)	Intrinsically Disordered Proteins/metabolism ; Protein Conformation
Chemical Substances	Intrinsically Disordered Proteins
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2024.02.023
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Article: Non-canonical functions of enhancers: regulation of RNA polymerase III transcription, DNA replication, and V(D)J recombination.

Struhl, Kevin

Trends in genetics : TIG

2024

Abstract: Enhancers are the key regulators of other DNA-based processes by virtue of their unique ability to generate nucleosome-depleted regions in a highly regulated manner. Enhancers regulate cell-type-specific transcription of tRNA genes by RNA polymerase III ( ...

Abstract	Enhancers are the key regulators of other DNA-based processes by virtue of their unique ability to generate nucleosome-depleted regions in a highly regulated manner. Enhancers regulate cell-type-specific transcription of tRNA genes by RNA polymerase III (Pol III). They are also responsible for the binding of the origin replication complex (ORC) to DNA replication origins, thereby regulating origin utilization, replication timing, and replication-dependent chromosome breaks. Additionally, enhancers regulate V(D)J recombination by increasing access of the recombination-activating gene (RAG) recombinase to target sites and by generating non-coding enhancer RNAs and localized regions of trimethylated histone H3-K4 recognized by the RAG2 PHD domain. Thus, enhancers represent the first step in decoding the genome, and hence they regulate biological processes that, unlike RNA polymerase II (Pol II) transcription, do not have dedicated regulatory proteins.
Language	English
Publishing date	2024-04-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2024.04.001
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Article ; Online: How is polyadenylation restricted to 3'-untranslated regions?

Struhl, Kevin

Yeast (Chichester, England)

2023 Volume 41, Issue 4, Page(s) 186–191

Abstract: Polyadenylation occurs at numerous sites within 3'-untranslated regions (3'-UTRs) but rarely within coding regions. How does Pol II travel through long coding regions without generating poly(A) sites, yet then permits promiscuous polyadenylation once it ... ...

Abstract	Polyadenylation occurs at numerous sites within 3'-untranslated regions (3'-UTRs) but rarely within coding regions. How does Pol II travel through long coding regions without generating poly(A) sites, yet then permits promiscuous polyadenylation once it reaches the 3'-UTR? The cleavage/polyadenylation (CpA) machinery preferentially associates with 3'-UTRs, but it is unknown how its recruitment is restricted to 3'-UTRs during Pol II elongation. Unlike coding regions, 3'-UTRs have long AT-rich stretches of DNA that may be important for restricting polyadenylation to 3'-UTRs. Recognition of the 3'-UTR could occur at the DNA (AT-rich), RNA (AU-rich), or RNA:DNA hybrid (rU:dA- and/or rA:dT-rich) level. Based on the nucleic acid critical for 3'-UTR recognition, there are three classes of models, not mutually exclusive, for how the CpA machinery is selectively recruited to 3'-UTRs, thereby restricting where polyadenylation occurs: (1) RNA-based models suggest that the CpA complex directly (or indirectly through one or more intermediary proteins) binds long AU-rich stretches that are exposed after Pol II passes through these regions. (2) DNA-based models suggest that the AT-rich sequence affects nucleosome depletion or the elongating Pol II machinery, resulting in dissociation of some elongation factors and subsequent recruitment of the CpA machinery. (3) RNA:DNA hybrid models suggest that preferential destabilization of the Pol II elongation complex at rU:dA- and/or rA:dT-rich duplexes bridging the nucleotide addition and RNA exit sites permits preferential association of the CpA machinery with 3'-UTRs. Experiments to provide evidence for one or more of these models are suggested.
MeSH term(s)	Polyadenylation ; 3' Untranslated Regions ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; DNA/metabolism
Chemical Substances	3' Untranslated Regions ; RNA Polymerase II (EC 2.7.7.-) ; DNA (9007-49-2)
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632636-5
ISSN	1097-0061 ; 0749-503X
ISSN (online)	1097-0061
ISSN	0749-503X
DOI	10.1002/yea.3915
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Article ; Online: Condition-specific 3' mRNA isoform half-lives and stability elements in yeast.

Geisberg, Joseph V / Moqtaderi, Zarmik / Struhl, Kevin

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 18, Page(s) e2301117120

Abstract: Alternative polyadenylation generates numerous 3' mRNA isoforms that can differ in their stability, structure, and function. These isoforms can be used to map mRNA stabilizing and destabilizing elements within 3' untranslated regions (3'UTRs). Here, we ... ...

Abstract	Alternative polyadenylation generates numerous 3' mRNA isoforms that can differ in their stability, structure, and function. These isoforms can be used to map mRNA stabilizing and destabilizing elements within 3' untranslated regions (3'UTRs). Here, we examine how environmental conditions affect 3' mRNA isoform turnover and structure in yeast cells on a transcriptome scale. Isoform stability broadly increases when cells grow more slowly, with relative half-lives of most isoforms being well correlated across multiple conditions. Surprisingly, dimethyl sulfate probing reveals that individual 3' isoforms have similar structures across different conditions, in contrast to the extensive structural differences that can exist between closely related isoforms in an individual condition. Unexpectedly, most mRNA stabilizing and destabilizing elements function only in a single growth condition. The genes associated with some classes of condition-specific stability elements are enriched for different functional categories, suggesting that regulated mRNA stability might contribute to adaptation to different growth environments. Condition-specific stability elements do not result in corresponding condition-specific changes in steady-state mRNA isoform levels. This observation is consistent with a compensatory mechanism between polyadenylation and stability, and it suggests that condition-specific mRNA stability elements might largely reflect condition-specific regulation of mRNA 3' end formation.
MeSH term(s)	Saccharomyces cerevisiae/metabolism ; RNA Isoforms ; Transcription, Genetic ; Polyadenylation ; Protein Isoforms/genetics ; RNA, Messenger/metabolism ; 3' Untranslated Regions ; RNA Stability/genetics
Chemical Substances	RNA Isoforms ; Protein Isoforms ; RNA, Messenger ; 3' Untranslated Regions
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2301117120
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Article ; Online: Functional analysis of a random-sequence chromosome reveals a high level and the molecular nature of transcriptional noise in yeast cells.

Gvozdenov, Zlata / Barcutean, Zeno / Struhl, Kevin

Molecular cell

2023 Volume 83, Issue 11, Page(s) 1786–1797.e5

Abstract: We measure transcriptional noise in yeast by analyzing chromatin structure and transcription of an 18-kb region of DNA whose sequence was randomly generated. Nucleosomes fully occupy random-sequence DNA, but nucleosome-depleted regions (NDRs) are much ... ...

Abstract	We measure transcriptional noise in yeast by analyzing chromatin structure and transcription of an 18-kb region of DNA whose sequence was randomly generated. Nucleosomes fully occupy random-sequence DNA, but nucleosome-depleted regions (NDRs) are much less frequent, and there are fewer well-positioned nucleosomes and shorter nucleosome arrays. Steady-state levels of random-sequence RNAs are comparable to yeast mRNAs, although transcription and decay rates are higher. Transcriptional initiation from random-sequence DNA occurs at numerous sites, indicating very low intrinsic specificity of the RNA Pol II machinery. In contrast, poly(A) profiles of random-sequence RNAs are roughly comparable to those of yeast mRNAs, suggesting limited evolutionary restraints on poly(A) site choice. Random-sequence RNAs show higher cell-to-cell variability than yeast mRNAs, suggesting that functional elements limit variability. These observations indicate that transcriptional noise occurs at high levels in yeast, and they provide insight into how chromatin and transcription patterns arise from the evolved yeast genome.
MeSH term(s)	Nucleosomes/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Chromatin/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Transcription, Genetic
Chemical Substances	Nucleosomes ; Chromatin ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.04.010
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Article ; Online: S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation.

Song, Ruisheng / Struhl, Kevin

Science advances

2021 Volume 7, Issue 1

Abstract: Cytokines are extracellular proteins that convey messages between cells by interacting with cognate receptors at the cell surface and triggering signaling pathways that alter gene expression and other phenotypes in an autocrine or paracrine manner. Here, ...

Abstract	Cytokines are extracellular proteins that convey messages between cells by interacting with cognate receptors at the cell surface and triggering signaling pathways that alter gene expression and other phenotypes in an autocrine or paracrine manner. Here, we show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers in a model of breast cellular transformation. This recruitment is associated with multiple DNA sequence motifs recognized by DNA binding transcription factors that are linked to transcriptional activation and are important for transformation. The cytokines interact with these transcription factors in nuclear extracts, and they activate transcription when artificially recruited to a target promoter. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional coactivator.
MeSH term(s)	Breast/pathology ; Calgranulin A/genetics ; Calgranulin A/metabolism ; Calgranulin B/genetics ; Calgranulin B/metabolism ; Cell Transformation, Neoplastic ; Cytokines/metabolism ; Humans ; Transcription Factors/metabolism
Chemical Substances	Calgranulin A ; Calgranulin B ; Cytokines ; S100A8 protein, human ; S100A9 protein, human ; Transcription Factors
Language	English
Publishing date	2021-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abe5357
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Article ; Online: Different SP1 binding dynamics at individual genomic loci in human cells.

Hasegawa, Yuko / Struhl, Kevin

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 46

Abstract: Using a tamoxifen-inducible time-course ChIP-sequencing (ChIP-seq) approach, we show that the ubiquitous transcription factor SP1 has different binding dynamics at its target sites in the human genome. SP1 very rapidly reaches maximal binding levels at ... ...

Abstract	Using a tamoxifen-inducible time-course ChIP-sequencing (ChIP-seq) approach, we show that the ubiquitous transcription factor SP1 has different binding dynamics at its target sites in the human genome. SP1 very rapidly reaches maximal binding levels at some sites, but binding kinetics at other sites is biphasic, with rapid half-maximal binding followed by a considerably slower increase to maximal binding. While ∼70% of SP1 binding sites are located at promoter regions, loci with slow SP1 binding kinetics are enriched in enhancer and Polycomb-repressed regions. Unexpectedly, SP1 sites with fast binding kinetics tend to have higher quality and more copies of the SP1 sequence motif. Different cobinding factors associate near SP1 binding sites depending on their binding kinetics and on their location at promoters or enhancers. For example, NFY and FOS are preferentially associated near promoter-bound SP1 sites with fast binding kinetics, whereas DNA motifs of ETS and homeodomain proteins are preferentially observed at sites with slow binding kinetics. At promoters but not enhancers, proteins involved in sumoylation and PML bodies associate more strongly with slow SP1 binding sites than with the fast binding sites. The speed of SP1 binding is not associated with nucleosome occupancy, and it is not necessarily coupled to higher transcriptional activity. These results with SP1 are in contrast to those of human TBP, indicating that there is no common mechanism affecting transcription factor binding kinetics. The biphasic kinetics at some SP1 target sites suggest the existence of distinct chromatin states at these loci in different cells within the overall population.
MeSH term(s)	Binding Sites/genetics ; Chromatin/genetics ; Genome, Human/genetics ; Genomics/methods ; Humans ; Nucleotide Motifs/genetics ; Promoter Regions, Genetic/genetics ; Protein Binding/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Sp1 Transcription Factor/genetics ; Transcription, Genetic/genetics
Chemical Substances	Chromatin ; Sp1 Transcription Factor ; SP1 protein, human
Language	English
Publishing date	2021-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2113579118
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Article ; Online: Comparison of transcriptional initiation by RNA polymerase II across eukaryotic species.

Petrenko, Natalia / Struhl, Kevin

eLife

2021 Volume 10

Abstract: The preinitiation complex (PIC) for transcriptional initiation by RNA polymerase (Pol) II is composed of general transcription factors that are highly conserved. However, analysis of ChIP-seq datasets reveals kinetic and compositional differences in the ... ...

Abstract	The preinitiation complex (PIC) for transcriptional initiation by RNA polymerase (Pol) II is composed of general transcription factors that are highly conserved. However, analysis of ChIP-seq datasets reveals kinetic and compositional differences in the transcriptional initiation process among eukaryotic species. In yeast, Mediator associates strongly with activator proteins bound to enhancers, but it transiently associates with promoters in a form that lacks the kinase module. In contrast, in human, mouse, and fly cells, Mediator with its kinase module stably associates with promoters, but not with activator-binding sites. This suggests that yeast and metazoans differ in the nature of the dynamic bridge of Mediator between activators and Pol II and the composition of a stable inactive PIC-like entity. As in yeast, occupancies of TATA-binding protein (TBP) and TBP-associated factors (Tafs) at mammalian promoters are not strictly correlated. This suggests that within PICs, TFIID is not a monolithic entity, and multiple forms of TBP affect initiation at different classes of genes. TFIID in flies, but not yeast and mammals, interacts strongly at regions downstream of the initiation site, consistent with the importance of downstream promoter elements in that species. Lastly, Taf7 and the mammalian-specific Med26 subunit of Mediator also interact near the Pol II pause region downstream of the PIC, but only in subsets of genes and often not together. Species-specific differences in PIC structure and function are likely to affect how activators and repressors affect transcriptional activity.
MeSH term(s)	Animals ; Cell Line ; Databases, Genetic ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/enzymology ; Drosophila melanogaster/genetics ; Gene Expression Regulation, Fungal ; Humans ; Mediator Complex/chemistry ; Mediator Complex/genetics ; Mediator Complex/metabolism ; Mice ; Promoter Regions, Genetic ; Protein Conformation ; RNA Polymerase II/chemistry ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Species Specificity ; Structure-Activity Relationship ; TATA-Binding Protein Associated Factors/genetics ; TATA-Binding Protein Associated Factors/metabolism ; TATA-Box Binding Protein/genetics ; TATA-Box Binding Protein/metabolism ; Transcription Factors, General/chemistry ; Transcription Factors, General/genetics ; Transcription Factors, General/metabolism ; Transcription Initiation Site ; Transcription Initiation, Genetic
Chemical Substances	Drosophila Proteins ; Mediator Complex ; Saccharomyces cerevisiae Proteins ; TATA-Binding Protein Associated Factors ; TATA-Box Binding Protein ; Transcription Factors, General ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2021-09-13
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.67964
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Article ; Online: A compensatory link between cleavage/polyadenylation and mRNA turnover regulates steady-state mRNA levels in yeast.

Moqtaderi, Zarmik / Geisberg, Joseph V / Struhl, Kevin

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 4

Abstract: Cells have compensatory mechanisms to coordinate the rates of major biological processes, thereby permitting growth in a wide variety of conditions. Here, we uncover a compensatory link between cleavage/polyadenylation in the nucleus and messenger RNA ( ... ...

Abstract	Cells have compensatory mechanisms to coordinate the rates of major biological processes, thereby permitting growth in a wide variety of conditions. Here, we uncover a compensatory link between cleavage/polyadenylation in the nucleus and messenger RNA (mRNA) turnover in the cytoplasm. On a global basis, same-gene 3' mRNA isoforms with twofold or greater differences in half-lives have steady-state mRNA levels that differ by significantly less than a factor of 2. In addition, increased efficiency of cleavage/polyadenylation at a specific site is associated with reduced stability of the corresponding 3' mRNA isoform. This inverse relationship between cleavage/polyadenylation and mRNA isoform half-life reduces the variability in the steady-state levels of mRNA isoforms, and it occurs in all four growth conditions tested. These observations suggest that during cleavage/polyadenylation in the nucleus, mRNA isoforms are marked in a manner that persists upon translocation to the cytoplasm and affects the activity of mRNA degradation machinery, thus influencing mRNA stability.
MeSH term(s)	3' Untranslated Regions ; Polyadenylation ; RNA Cleavage ; RNA Isoforms ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Yeasts/genetics ; Yeasts/metabolism
Chemical Substances	3' Untranslated Regions ; RNA Isoforms ; RNA, Messenger
Language	English
Publishing date	2022-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2121488119
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