Publication highlights

The MRTF-SRF and the YAP-TEAD transcriptional regulatory networks both respond to extracellular signals and mechanical stimuli: the MRTFs are controlled directly by G-actin, while YAP activity is somehow potentiated by F-actin. Cancer-associated fibroblasts play an important pro-invasive role in stimulating cancer progression, and previous studies have shown that this involves YAP-TEAD signalling. This paper shows that CAFs also exhibit mechanically-dependent MRTF activation, which is also required for their contractile and pro-invasive activity. The two pathways are mutually dependent, requiring recruitment of MRTF and YAP to DNA via their respective DNA-binding partners, and reflecting their ability to control cytoskeletal gene expression.

This paper shows that the ArhGAP9/12/15/27 and ArhGAP32/33 families of rhoGAPs are RPEL proteins whose activity is coupled to G-actin concentration. G-actin forms a 1:1 complex with these ArhGAPs, interacting with an RPEL motif located between the PH and GAP domains, thereby inhibiting their GAP activity. Mutations that block G-actin binding exhibit elevated GAP activity towards their substrate GTPases Rac and Cdc42. Strikingly, treatment of cells with drugs enhancing or inhibiting G-actin/ArhGAP interaction has corresponding effects on Rac GTP loading. These results establish a novel homeostatic feedback loop, in which ArhGAP12-family (and presumably ArhGAP32-family) GAP activity increases when G-actin levels become limiting.

This is the first prospective study in any cancer type that resolved the origin of the metastasising clone in the primary tumour characterising its genetic features and uncovering high risk events that confer risk of death.

This is the largest genomic study ever to be conducted in renal cell cancer and the first to show how evolutionary features of the tumour impact the clinical phenotype. Patent arising.

In this study we showed that the Dp1Tyb mouse model of DS has locomotor defects, mapped the causative genes to a 25-gene region and identified that Dyrk1a is one of these. Furthermore, we found an unexpected progressive loss of motor neurons in these mice and showed that a similar loss is seen in humans with DS.

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.

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.

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 show that the clustering of cancer cells following detachment from ECM results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis.

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.

Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. This is the first vaccine against tuberculosis to be shown effective in humans since the advent of BCG in 1921. A product development and further testing plan has recently been agreed and we will contribute to the latter.