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Transcriptional elongation factor Paf1 core complex adopts a spirally wrapped solenoidal topology
Deng, Pujuan,Zhou, Yuqiao,Jiang, Junyi,Li, Haojie,Tian, Wei,Cao, Yinghua,Qin, Yan,Kim, Jaehoon,Roeder, Robert G.,Patel, Dinshaw J.,Wang, Zhanxin National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.40
<▼1><P><B>Significance</B></P><P>The polymerase-associated factor 1 (PAF1) complex is a general transcription elongation factor of RNA polymerase II, which not only regulates various stages of the transcription cycle but also broadly influences gene expression through modulating chromatin structure and/or recruiting other transcription-related factors. This study presents a high-resolution crystal structure of the core region of the Paf1-Ctr9-Cdc73 ternary complex, which not only greatly facilitates our understanding of the overall architecture of the Paf1 complex but also provides a structure-based platform for understanding the molecular mechanism underlying the role of the Paf1 complex in regulating gene expression and sheds light toward deciphering the impact of its mutational spectrum on human diseases.</P></▼1><▼2><P>The polymerase-associated factor 1 (Paf1) complex is a general transcription elongation factor of RNA polymerase II, which is composed of five core subunits, Paf1, Ctr9, Cdc73, Leo1, and Rtf1, and functions as a diverse platform that broadly affects gene expression genome-wide. In this study, we solved the 2.9-Å crystal structure of the core region composed of the Ctr9-Paf1-Cdc73 ternary complex from a thermophilic fungi, which provides a structural perspective of the molecular details of the organization and interactions involving the Paf1 subunits in the core complex. We find that Ctr9 is composed of 21 tetratricopeptide repeat (TPR) motifs that wrap three circular turns in a right-handed superhelical manner around the N-terminal region of an elongated single-polypeptide–chain scaffold of Paf1. The Cdc73 fragment is positioned within the surface groove of Ctr9, where it contacts mainly with Ctr9 and minimally with Paf1. We also identified that the Paf1 complex preferentially binds single-strand–containing DNAs. Our work provides structural insights into the overall architecture of the Paf1 complex and paves the road forward for understanding the molecular mechanisms of the Paf1 complex in transcriptional regulation.</P></▼2>
Josefowicz, Steven Z.,Shimada, M.,Armache, A.,Li, Charles H.,Miller, Rand M.,Lin, S.,Yang, A.,Dill, Brian D.,Molina, H.,Park, H.S.,Garcia, Benjamin A.,Taunton, J.,Roeder, Robert G.,Allis, C. Cell Press 2016 Molecular cell Vol.64 No.2
<P>The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen-and stress-activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription.</P>