Patrick Cramer
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View article: Molecular mechanism of co-transcriptional H3K36 methylation by SETD2
Molecular mechanism of co-transcriptional H3K36 methylation by SETD2 Open
H3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II. H…
View article: IWS1 positions downstream DNA to globally stimulate Pol II elongation
IWS1 positions downstream DNA to globally stimulate Pol II elongation Open
The protein IWS1 (Interacts with SPT6 1) is implicated in transcription-associated processes, but a direct role in RNA polymerase (Pol) II function is unknown. Here, we use multi-omics kinetic analysis after rapid depletion of IWS1 in huma…
View article: Chemical crosslinking extends and complements UV crosslinking in analysis of RNA/DNA nucleic acid–protein interaction sites by mass spectrometry
Chemical crosslinking extends and complements UV crosslinking in analysis of RNA/DNA nucleic acid–protein interaction sites by mass spectrometry Open
Ultraviolet (UV) crosslinking with mass spectrometry (XL-MS) has been established for identifying RNA- and DNA-binding proteins along with their domains and amino acids involved. Here, we explore chemical XL-MS for RNA–protein, DNA–protein…
View article: Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex
Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex Open
In eukaryotic cells, splicing occurs predominantly co-transcriptionally, enhancing splicing efficiency and fidelity while introducing an additional layer of regulation over gene expression. RNA polymerase II (Pol II) facilitates co-transcr…
View article: Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex
Structure of a transcribing Pol II-DSIF-SPT6-U1 snRNP complex Open
RNA polymerase II (Pol II) facilitates co-transcriptional splicing by recruiting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) to the nascent transcripts. Here, we report the cryo-electron microscopy structure of a transcribin…
View article: Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr
Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr Open
Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdR…
View article: Promoter-proximal RNA polymerase II termination regulates transcription during human cell type transition
Promoter-proximal RNA polymerase II termination regulates transcription during human cell type transition Open
Metazoan gene transcription by RNA polymerase II (Pol II) is regulated in the promoter-proximal region. Pol II can undergo termination in the promoter-proximal region but whether this can contribute to transcription regulation in cells rem…
View article: STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair
STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair Open
Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) aro…
View article: Mechanism of polyadenylation-independent RNA polymerase II termination
Mechanism of polyadenylation-independent RNA polymerase II termination Open
The mechanisms underlying the initiation and elongation of RNA polymerase II (Pol II) transcription are well-studied, whereas termination remains poorly understood. Here we analyze the mechanism of polyadenylation-independent Pol II termin…
View article: Resolution of transcription-induced hexasome-nucleosome complexes by Chd1 and FACT
Resolution of transcription-induced hexasome-nucleosome complexes by Chd1 and FACT Open
To maintain the nucleosome organization of transcribed genes, ATP-dependent chromatin remodelers collaborate with histone chaperones. Here, we show that at the 5' ends of yeast genes, RNA polymerase II (RNAPII) generates hexasomes that occ…
View article: Chemical crosslinking extends and complements UV crosslinking in analysis of RNA/DNA nucleic acid–protein interaction sites by mass spectrometry
Chemical crosslinking extends and complements UV crosslinking in analysis of RNA/DNA nucleic acid–protein interaction sites by mass spectrometry Open
UV (ultra-violet) crosslinking with mass spectrometry (XL-MS) has been established for identifying RNA- and DNA-binding proteins along with their domains and amino acids involved. Here, we explore chemical XL-MS for RNA-protein, DNA-protei…
View article: Mechanism of Co-Transcriptional Cap-Snatching by Influenza Polymerase
Mechanism of Co-Transcriptional Cap-Snatching by Influenza Polymerase Open
Influenza virus mRNA is stable and competent for nuclear export and translation because it receives a 5′ cap(1) structure in a process called cap-snatching 1 . During cap-snatching, the viral RNA-dependent RNA polymerase (FluPol) binds to …
View article: STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair
STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair Open
Summary Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and TFIIH around lesion-stalled …
View article: FACT maintains chromatin architecture and thereby stimulates RNA polymerase II pausing during transcription in vivo
FACT maintains chromatin architecture and thereby stimulates RNA polymerase II pausing during transcription in vivo Open
Facilitates chromatin transcription (FACT) is a histone chaperone that supports transcription through chromatin in vitro, but its functional roles in vivo remain unclear. Here, we analyze the in vivo functions of FACT with the use of multi…
View article: The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2
The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2 Open
Phenotypic assays detect small‐molecule bioactivity at functionally relevant cellular sites, and inherently cover a variety of targets and mechanisms of action. They can uncover new small molecule‐target pairs and may give rise to novel bi…
View article: The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2
The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2 Open
Phenotypic assays detect small‐molecule bioactivity at functionally relevant cellular sites, and inherently cover a variety of targets and mechanisms of action. They can uncover new small molecule‐target pairs and may give rise to novel bi…
View article: The pioneer transcription factor ELF2 remodels the nucleosome near transcription start sites
The pioneer transcription factor ELF2 remodels the nucleosome near transcription start sites Open
Pioneer transcription factors are DNA-binding proteins that can bind to nucleosomes in closed chromatin regions, exposing enhancers and promoters of genes for transcription. The action of these factors underpin stem cell pluripotency, cell…
View article: Three-step mechanism of promoter escape by RNA polymerase II
Three-step mechanism of promoter escape by RNA polymerase II Open
The transition from transcription initiation to elongation is highly regulated in human cells but remains incompletely understood at the structural level. In particular, it is unclear how interactions between RNA polymerase II (RNA Pol II)…
View article: Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair
Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair Open
During transcription-coupled DNA repair (TCR), RNA polymerase II (Pol II) transitions from a transcriptionally active state to an arrested state that allows for removal of DNA lesions. This transition requires site-specific ubiquitylation …
View article: RNA polymerase II elongation factors use conserved regulatory mechanisms
RNA polymerase II elongation factors use conserved regulatory mechanisms Open
RNA polymerase II (Pol II) transcription is regulated by many elongation factors. Among these factors, TFIIF, PAF-RTF1, ELL and Elongin stimulate mRNA chain elongation by Pol II. Cryo-EM structures of Pol II complexes with these elongation…
View article: Three-step mechanism of promoter escape by RNA polymerase II
Three-step mechanism of promoter escape by RNA polymerase II Open
SUMMARY The transition from transcription initiation to elongation is highly regulated in human cells but remains incompletely understood at the structural level. In particular, it is unclear how interactions between RNA polymerase (Pol) I…
View article: MSL2 ensures biallelic gene expression in mammals
MSL2 ensures biallelic gene expression in mammals Open
In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA 1,2 . This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developm…
View article: Structure of the transcribing RNA polymerase II–Elongin complex
Structure of the transcribing RNA polymerase II–Elongin complex Open
Elongin is a heterotrimeric elongation factor for RNA polymerase (Pol) II transcription that is conserved among metazoa. Here, we report three cryo-EM structures of human Elongin bound to transcribing Pol II. The structures show that Elong…
View article: Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells
Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells Open
Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30–40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel thera…
View article: Structural insights into human co-transcriptional capping
Structural insights into human co-transcriptional capping Open
Co-transcriptional capping of the nascent pre-mRNA 5' end prevents degradation of RNA polymerase (Pol) II transcripts and suppresses the innate immune response. Here, we provide mechanistic insights into the three major steps of human co-t…