Structure of the human SAGA coactivator complex: The divergent architecture of human SAGA allows modular coordination of transcription activation and co-transcriptional splicing

Nogales, Eva; Herbst, D.A.; Esbin, Meagan; Louder, Robert K.; Dugast-Darzacq, Claire; Dailey, Gina M; Fang, Qianglin; Darzacq, Xavier; Tjian, Robert

doi:10.1101/2021.02.08.430339

Cited by 11 publications

(16 citation statements)

References 86 publications

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“…Taken together, these results suggest that TRRAP does not have a major contribution to SAGA integrity and function at these genes. Thus, despite its large size and absence of catalytic activity, TRRAP is presumably not a core subunit of SAGA in human cells, consistent with recent structural studies revealing its peripheral localization within the complex (59)(60)(61).…”

Section: Saga Regulates Unfolded Protein Response Genes Independently Of Trrapsupporting

confidence: 86%

The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Detilleux

Raynaud

Pradet‐Balade

et al. 2021

Preprint

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Transcription is essential for cells to respond to signaling cues and involves factors with multiple distinct activities. One such factor, TRRAP, functions as part of two large complexes, SAGA and TIP60, which have crucial roles during transcription activation. Structurally, TRRAP belongs to the PIKK family but is the only member classified as a pseudokinase. Recent studies established that a dedicated HSP90 co-chaperone, the TTT complex, is essential for PIKK stabilization and activity. Here, using endogenous auxin-inducible degron alleles, we show that the TTT subunit TELO2 promotes TRRAP assembly into SAGA and TIP60 in human colorectal cancer cells (CRC). Transcriptomic analysis revealed that TELO2 contributes to TRRAP regulatory roles in CRC cells, most notably of MYC target genes. Surprisingly, TELO2 and TRRAP depletion also induced the expression of type I interferon genes. Using a combination of nascent RNA, antibody-targeted chromatin profiling (CUT&RUN) and kinetic analyses, we show that TRRAP directly represses the expression of IRF9, which is a master regulator of interferon stimulated genes. We have therefore uncovered a new, unexpected transcriptional repressor role for TRRAP, which may contribute to its tumorigenic activity.

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Section: Saga Regulates Unfolded Protein Response Genes Independently Of Trrapsupporting

confidence: 86%

The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Detilleux

Raynaud

Pradet‐Balade

et al. 2021

Preprint

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“…Deletion of yeast KAT or DUB module subunits only interfered with the assembly of the corresponding module. Recent structural studies by high resolution cryo-electron microscopy revealed that the connections of the core module to the two enzymatic modules are considerably flexible in both yeast and human SAGA complexes [ 22 , 23 , 33 ]. The carboxyl-terminal part of Sgf73 is embedded in the core module, thereby tethering the DUB module to the remainder of SAGA.…”

Section: Saga Composition Across Kingdomsmentioning

confidence: 99%

“…Unlike other GCN5-containing complexes such as the metazoan-specific ATAC complex, SAGA is uniquely conserved in all eukaryotes. The recently elucidated high-resolution structures of SAGA from two yeast genera and from humans enlightened our understanding of its dynamic conformation in unicellular and higher eukaryotes [ 22 , 23 , 33 ]. Attributable to its intrinsic large composition and structural flexibility of the KAT and DUB modules in relation to the core module, each module may have independent roles in the process of transcriptional regulation, which is consistent with different impacts to gene expression profiles upon mutation of components belonging to separate modules [ 70 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Conservation and diversity of the eukaryotic SAGA coactivator complex across kingdoms

Chen

Dent

2021

Epigenetics & Chromatin

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The SAGA complex is an evolutionarily conserved transcriptional coactivator that regulates gene expression through its histone acetyltransferase and deubiquitylase activities, recognition of specific histone modifications, and interactions with transcription factors. Multiple lines of evidence indicate the existence of distinct variants of SAGA among organisms as well as within a species, permitting diverse functions to dynamically regulate cellular pathways. Our co-expression analysis of genes encoding human SAGA components showed enrichment in reproductive organs, brain tissues and the skeletal muscle, which corresponds to their established roles in developmental programs, emerging roles in neurodegenerative diseases, and understudied functions in specific cell types. SAGA subunits modulate growth, development and response to various stresses from yeast to plants and metazoans. In metazoans, SAGA further participates in the regulation of differentiation and maturation of both innate and adaptive immune cells, and is associated with initiation and progression of diseases including a broad range of cancers. The evolutionary conservation of SAGA highlights its indispensable role in eukaryotic life, thus deciphering the mechanisms of action of SAGA is key to understanding fundamental biological processes throughout evolution. To illuminate the diversity and conservation of this essential complex, here we discuss variations in composition, essentiality and co-expression of component genes, and its prominent functions across Fungi, Plantae and Animalia kingdoms.

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“…The modified GO coating method has been used with several other samples of varying size, and typically resulted in reconstructions with better than 3Å resolution 54 ( to be published ). However, it should be noted that in these other cases, tilting was not required.…”

Section: Introductionmentioning

confidence: 99%

Efficient graphene oxide coating improves cryo-EM sample preparation and data collection from tilted grids

Patel¹,

Toso²,

Litvak

et al. 2021

Preprint

Self Cite

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Recent technical developments have made single particle cryo-EM a major structural biology technique, especially in the characterization of challenging samples that resist crystallization, can only be obtained in small amounts, or suffer from compositional or conformational heterogeneity. However, a number of hurdles that often challenge sample preparation still need to be overcome in order to increase the applicability and throughput of cryo-EM. These technical hurdles include obtaining enough particles per image, with close to random orientation, and without damage from interaction with the air-water interface. While coating EM grids with graphene oxide is a promising procedure for the improvement of sample preparation, it suffers from some technical problems that limit its applicability. We have modified the established drop cast method for adhering graphene oxide onto holey patterned grids to increase graphene coverage. Our method relies on the use of a polycationic polymer to coat the surface of the grid prior to graphene oxide application, thereby preventing the repulsion of the negatively charged graphene oxide sheets from the negatively charged grid surface. With this improved preparation method, we show that graphene oxide supports can increase the number of particles in the field of view by an order of magnitude with respect to open holes, while keeping them away from the damaging air-water interface. We also show how graphene oxide coated gold foil grids can be used to collect tilted cryo-EM data in order to overcome preferred orientation issues, without experiencing the large amount of drift observed with conventional amorphous carbon supports, thus allowing data collection that can lead to high-resolution reconstructions.

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Structure of the human SAGA coactivator complex: The divergent architecture of human SAGA allows modular coordination of transcription activation and co-transcriptional splicing

Cited by 11 publications

References 86 publications

The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

Conservation and diversity of the eukaryotic SAGA coactivator complex across kingdoms

Efficient graphene oxide coating improves cryo-EM sample preparation and data collection from tilted grids

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