Nicolas H. Thomä
YOU?
Author Swipe
View article: E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility
E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility Open
Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reen…
View article: Tandem association of CLOCK:BMAL1 complexes on DNA enables recruitment of CBP/p300 through multivalent interactions
Tandem association of CLOCK:BMAL1 complexes on DNA enables recruitment of CBP/p300 through multivalent interactions Open
The basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor CLOCK:BMAL1 interacts with E-box motifs in the context of nucleosomes to elicit a circadian pattern of gene expression that oscillates with approximately 24 hour perio…
View article: Opportunities in proximity modulation: Bridging academia and industry
Opportunities in proximity modulation: Bridging academia and industry Open
In the past decade, exciting therapeutic strategies to harness the ubiquitin-proteasome system (UPS) for degradation of target proteins have emerged. Proximity-inducing modalities are at the center of these strategies and act by modulating…
View article: Nucleosomes specify co-factor access to p53
Nucleosomes specify co-factor access to p53 Open
Pioneer transcription factors (TFs) engage chromatinized DNA motifs. However, it is unclear how the resultant TF-nucleosome complexes are decoded by co-factors. In humans, the TF p53 regulates cell-cycle progression, apoptosis, and the DNA…
View article: Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders
Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders Open
Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease‐related proteins. While molecular glue degraders exhibit drug‐like properties, their discovery has traditionally been serendipi…
View article: BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma
BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma Open
Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). The core circadian transcription f…
View article: Primed for degradation: How weak protein interactions enable molecular glue degraders
Primed for degradation: How weak protein interactions enable molecular glue degraders Open
Molecular glues are small drug-like molecules that induce de novo protein-protein interactions or facilitate pre-existing weak interactions between proteins. In the context of a ubiquitin ligase, such binding events frequently result in ub…
View article: A Multicomponent Reaction-Based Platform Opens New Avenues in Aryl Hydrocarbon Receptor Modulation
A Multicomponent Reaction-Based Platform Opens New Avenues in Aryl Hydrocarbon Receptor Modulation Open
A multidisciplinary platform is presented to address aryl hydrocarbon receptor (AhR) modulation. A rewired Yonemitsu multicomponent reaction with indole 2-carboxaldehydes and nucleophilic species was designed to access a family of 6-substi…
View article: Niclosamide: CRL4<sup>AMBRA1</sup> mediated degradation of cyclin D1 following mitochondrial membrane depolarization
Niclosamide: CRL4<sup>AMBRA1</sup> mediated degradation of cyclin D1 following mitochondrial membrane depolarization Open
Niclosamide, an FDA-approved anthelmintic drug, known to uncouple the mitochondria induces cyclin D1 degradation via CRL4 AMBRA1 . We find a striking correlation between the two processes and that it is observed amongst various compounds.
View article: Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA
Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA Open
Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal DNA to…
View article: BMAL1-HIF2α heterodimers contribute to ccRCC
BMAL1-HIF2α heterodimers contribute to ccRCC Open
Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 …
View article: Epidemiological trends and susceptibility patterns of bloodstream infections caused by Enterococcus spp. in six German university hospitals: a prospectively evaluated multicentre cohort study from 2016 to 2020 of the R-Net study group
Epidemiological trends and susceptibility patterns of bloodstream infections caused by Enterococcus spp. in six German university hospitals: a prospectively evaluated multicentre cohort study from 2016 to 2020 of the R-Net study group Open
Purpose To analyse recent epidemiological trends of bloodstream infections (BSI) caused by Enterococcus spp. In adult patients admitted to tertiary care centres in Germany. Methods Epidemiological data from the multicentre R-NET study was …
View article: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance Open
Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug…
View article: Structural insights into viral hijacking of p53 by E6 and E6AP
Structural insights into viral hijacking of p53 by E6 and E6AP Open
The E3-ubiquitin ligase E6AP degrades p53 when complexed with the viral protein E6 from human papilloma virus (HPV), which contributes to the transformation of cells in HPV-related cancers. Previous crystal structures of the E6AP-E6-p53 te…
View article: Design principles for cyclin K molecular glue degraders
Design principles for cyclin K molecular glue degraders Open
Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–C…
View article: Orphan quality control shapes network dynamics and gene expression
Orphan quality control shapes network dynamics and gene expression Open
(Cell 186, 3460–3475.e1–e23; August 3, 2023) In the originally published version of this article, due to a copy-paste error, Figure 1B inadvertently showed the blot for MYC instead of BUBR1. This has since been corrected online. The author…
View article: From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation Open
Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for de…
View article: Orphan quality control shapes network dynamics and gene expression
Orphan quality control shapes network dynamics and gene expression Open
All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dyn…
View article: UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability
UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability Open
Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR…
View article: Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings
Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings Open
Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibitio…
View article: A deep dive into degrader-induced protein-protein interfaces
A deep dive into degrader-induced protein-protein interfaces Open
Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al. introduced…
View article: Readout of histone methylation by Trim24 locally restricts chromatin opening by p53
Readout of histone methylation by Trim24 locally restricts chromatin opening by p53 Open
The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dep…
View article: Quality control of protein complex assembly by the ubiquitin–proteasome system
Quality control of protein complex assembly by the ubiquitin–proteasome system Open
The majority of human proteins operate as multimeric complexes with defined compositions and distinct architectures. How the assembly of these complexes is surveyed and how defective complexes are recognized is just beginning to emerge. In…