Publication highlights

Building on our successful biochemical reconstitution of topological cohesin loading onto DNA, we completed the reconstitution of both dynamic loading as well as unloading. We realised that both loading and unloading follow a very similar trajectory through sequential ATPase and kleisin gates, only one of which can be open at any one time. This formed the basis for our unified DNA passage proposal both into and out of the ring.

Cohesin is a ring-shaped protein complex that topologically entraps DNA to fulfil key functions in chromosome architecture. In a collaborative and multidisciplinary approach, we used cryo-EM, biochemical and biophysical techniques to describe how ATP-fuelled structural changes of the cohesin complex drive the DNA entry reaction into the cohesin ring. This solves one of the outstanding riddles in molecular biology.

One of the major surprises of our iCLIP studies was the major role that transposable elements play as hubs for RNP assembly. Here, we uncover multiple roles of LINEs in RNP assembly, and show how this helps to create repressive environment in introns, while also driving the evolution of new tissue-specific exons.

We showed that active YAP1 in radial glia derived neural precursor cells induces ependymoma-like tumours in mice. We demonstrated that YAP1 is necessary and sufficient using mouse models. We found that transcription coactivator HOPX, a factor consistently suppressed in malignancies, is highly expressed in our mouse models and in YAP1-fusion human ependymoma. HOPX differentiates YAP1-fusion subtype from the highly malignant RELA-fusion human ependymomas. This supports the notion for subtype-specific care for ependymoma.

This study leverages molecular archaeology of cancer approaches in a large-scale pan-cancer setting to construct timelines of tumour evolution, showing when in a tumour’s evolutionary history key events typically happen. It demonstrates that tumours typically develop over multiple years to sometimes decades, highlighting opportunities for early detection.

Transcription factors typically activate transcription by recruiting cofactors, but our data in this paper illustrate a new function. We show that the sequence-specific transcription factor Rap1 prevents regulatory elements from initiating transcription in the divergent direction. We define a novel mechanism for providing directionality towards productive transcription, as Rap1 promotes directionality, at least in part, by directly interfering with transcription initiation in the divergent direction. Our study reveals a new important layer of regulation, describing how genomes restrict the accumulation of aberrant transcripts and ensure productive coding gene expression.

This paper solves the Wnt solubility problem, which has preoccupied the Wnt field for the past 15 years. It explains how the lipid of Wnts can be maintained in the extracellular space.

By merging the power of molecular genetics, basic physical chemistry and mathematical modeling we show quantitatively how an inert protein, GFP, can be turned into a morphogen that provides positional information in a developing tissue, the Drosophila wing disc. This is the first time that an active synthetic morphogen gradient has been reconstituted in vivo. Because the properties of the synthetic gradient can be experimentally modulated, a physical analysis of molecular determinants of morphogen gradients becomes possible.

In this paper we show that the ability of cells to survive glutamine depletion depends on aspartate metabolism, which is supported by the aspartate/glutamate transporter SLC1A3. The tumor suppressor p53 is shown to induce the expression of SLC1A3, explaining in part how p53 can help cancer cells survive under glutamine starvation.

We showed that interferons (IFNs), known to have antiviral effect, can aggravate respiratory viral infection if present late during infection when epithelial repair sets in. IFN-β and, most potently, IFN-λ reduce airway epithelial proliferation and differentiation in that recovery phase. This is important to understand the complex roles of IFNs in viral infections and has important implications for IFN treatments as presently discussed for COVID-19.

The Arp2/3 complex, consisting of seven evolutionarily conserved subunits, generates branched actin networks during many fundamental cellular processes. Taking advantage of actin based motility of Vaccinia virus as a model system, we demonstrate for the first time that in humans the Arp2/3 complex is actually a family of different complexes with distinct actin-nucleating properties.

The generation of CRISPR-Cas9 GEN1 k/o cell lines (supplemented with MUS81 siRNA) allowed us to develop the first model system to analyse the phenotypes of ‘resolvase-deficient’ human cells. We discovered that recombination intermediates persist until anaphase (despite the presence of the BLM-TopoIII-RMI1-RMI2 dissolvasome) where they form ultra-fine bridges (UFBs). These UFBs represent a new class of ultrafine bridges (we termed them HR-UFBs) distinct from replication stress induced UFBs or centromeric UFBs. HR-UFBs were targeted and processed by PICH/BLM, leading to the formation of ssDNA bridges that were broken at cytokinesis. Loss of GEN1 and MUS81 activity led to synthetic lethality.

This work used high-resolution PET/CT imaging to establish for the first time in humans the existence of a high-risk asymptomatic transition state between latent infection and active disease. The technique is thus a phenotypic benchmark for further experimental medicine studies of interventions to prevent progression of asymptomatic subclinical tuberculosis.