Publication highlights

A Crick researcher reading a scientific paper on a screen.

Intro

Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week. Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Highlights

Filter by year of publication

CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis

Intestinal homeostasis requires a continuous dialogue between commensal bacteria and intestinal immune cells. Natural Killer T (NKT) cells are a population of CD1d-restricted lipid-reactive lymphocytes contributing to the regulation of mucosal immunity, but the mechanisms underlying this are poorly understood. Here we show that lipid presentation by CD1d+ intestinal dendritic cells and macrophages controls NKT cell function and activation which in turn regulates commensal bacteria and immune cell populations in the gut. These results reveal an NKT cell-dendritic cell crosstalk as a key mechanism for the regulation of intestinal homeostasis.

View the publication

Published in EMBO Journal

Published

Phospho-dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction

This study explained the mechanism of SAMHD1 regulation by phosphorylation/tetramerisation and correlated restriction activity with the capacity of SAMHD1 to form long lived, stable tetramers. These data form the basis of the prevailing model for SAMHD1 restriction of HIV-1 where dNTP-stabilised SAMHD1 tetramers deplete and maintain low levels of dNTPs in the non-permissive cells resistant to HIV-1 infection.

View the publication

Published in PLOS Pathogens

Published

A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells

This study showed that egress involves an enzyme cascade in which the serine protease SUB1 activates a second, cysteine protease called SERA6, enabling SERA6 to rapidly and precisely cleave the major red cell cytoskeletal protein β-spectrin and dismantle the cytoskeleton. It provides the first plausible model to explain how the parasite accomplishes timely rupture of its host cell membrane.

View the publication

Published in Nature Microbiology

Published

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

Immunodeficient mouse models have been instrumental in improving our understanding of human healthy haemopoietic stem cells and their hierarchical organisation as well as of the functional and phenotypic heterogeneity of leukaemic stem cells in acute myeloid leukaemia. However, xenotransplantation models failed at reconstituting the human bone marrow niche which remains of mouse origin. Using a bioengineered scaffold, we developed a new versatile humanised bone marrow niche which supports the engraftment of both normal and leukaemia stem cells in vivo. This 3D scaffold represents a suitable model to study and dissect the human bone marrow composition and test the effect of specific stroma cell types and niche factor functions during both normal human haemopoiesis and leukaemia.

View the publication

Published in Journal of Clinical Investigation

Published

Stabilization of reversed replication forks by telomerase drives telomere catastrophe

This study defined the mechanism leading to critically short telomeres in the absence of RTEL1 and showed that telomerase, which extends telomeres in normal cells, is pathological when forks encounter an obstacle within the telomere. We showed that replication forks stall and reverse at persistent t-loops, which creates a pseudo-telomere substrate that is inappropriately stabilised by telomerase. Removing telomerase or blocking replication fork reversal rescued telomere dysfunction in Rtel1 deficient cells. We proposed that when persistent t-loops stall the replisome, telomerase inhibits fork restart, triggering the excision of the t-loop by SLX1/4 and loss of a substantial part of the telomere.

View the publication

Published in Cell

Published

Rad51 paralogs remodel pre-synaptic Rad51 filaments to stimulate homologous recombination

This study was the first to demonstrate that RAD51 paralogues bind to and structurally remodel the pre-synaptic RAD-51-ssDNA filament to a stabilised, “open”, and flexible conformation, which facilitates strand exchange with the template duplex. We showed that RAD51 paralogues act by binding the end of the presynaptic filament, which induces a conformational change that stabilises RAD-51 bound to ssDNA and primes the filament for strand exchange. These observations established for the first time the underlying mechanism of HR stimulation by Rad51 paralogues and revealed a new paradigm for the action of HR mediator proteins.

View the publication

Published in Cell

Published

Decoding of position in the developing neural tube from antiparallel morphogen gradients

Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. Using quantitative gene expression and signalling measurements we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. This revealed a strategy that minimises patterning errors in response to the joint input of noisy opposing gradients. The study illustrates how we integrate quantitative data, developmental and microfluidic experiments with phenological and mechanistic models.

View the publication

Published in Science

Published

Nervous system regionalization entails axial allocation before neural differentiation

The prevailing view of neural induction in vertebrate embryos had been that cells are initially induced with anterior (forebrain) identity and then caudalising signals convert a proportion to posterior fates (spinal cord). Using chromatin accessibility, to define how cells adopt region-specific neural fates, combined with genetic and biochemical perturbations, we found that contrary to the established model, cells commit to a regional identity before acquiring neural identity. These findings prompt a revision to textbook models of neural induction. The study illustrates our adoption of new genomic methods (ATACseq) to address long-standing questions, and our capacity to productively collaborate with computational biologists.

View the publication

Published in Cell

Published

A supramolecular assembly mediates lentiviral DNA integration

Lentiviral IN proteins are notoriously poorly behaved in vitro, and the HIV 1 intasome has eluded structural biologists for over two decades. Prior research resulted in a collection of partial crystal and NMR structures that did not explain how lentiviral integrase synapses viral DNA ends. This paper described the first structure of the lentiviral intasome, solving the long-standing mystery and reconciling years of HIV-1 integrase structural biology and biochemistry.

View the publication

Published in Science

Published

Structural basis for retroviral integration into nucleosomes

Here, we described a cryo-EM structure of a retroviral intasome in a functional complex with a nucleosome. The structure revealed a multivalent interface of the viral integration machinery and chromatin, involving both gyres of nucleosomal DNA and histones. Whilst the histone octamer remains intact, the DNA is lifted from its surface to allow for strand transfer at highly preferred integration sites. These data provided a unique snapshot of an enzyme recognizing and acting upon nucleosomal DNA. The structure was the first to illustrate nucleosome flexibility facilitating a biological process and, as such, had far-reaching implications for chromosome biology.

View the publication

Published in Nature

Published

Bidirectional eukaryotic DNA replication is established by quasi-symmetrical helicase loading

This paper shows that loading of the MCM double hexamer is a quasi-symmetrical reaction: two ORC molecules bound at two opposing sites of different affinity each recruit and load a single hexamer. The distance between the ORC binding sites is not critical. Subsequent work has provided further evidence for this from cryo-EM.

View the publication

Published in Science

Published

The mechanism of eukaryotic CMG helicase activation

This paper provided the first view of how the inactive MCM double hexamer is converted to two active CMG helicases. We showed MCM remains bound to ADP after loading; firing factors trigger ADP-ATP exchange; ATP rebinding causes double hexamer splitting, initial DNA melting and CMG formation. Active helicases then translocate N-terminus first.

View the publication

Published in Nature

Published

Chromatin controls DNA replication origin selection, lagging-strand synthesis, and replication fork rates

In this and the accompanying paper (Yeeles et al. 2017 Mol Cel 65, 105-116) we describe the reconstitution of full chromatin replication. We first identified all of the factors required for complete and rapid replication of naked DNA. Then we identified and characterised factors required to replicate chromatinised templates. We showed FACT is essential for chromatin replication, whilst nucleosome remodellers and histone acetylases help chromatin replication. In addition, chromatin enforces origin specificity and Okazaki fragment processing. Finally, we found that histones are efficiently transferred to nascent DNA.

View the publication

Published in Molecular Cell

Published

Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA

This work establishes for the first time a link between oncogenic RAS signalling and increased immuno-suppressive expression of the immune checkpoint protein PD-L1. RAS signalling results in phosphorylation and inactivation of TTP, a factor involved in degrading PD-L1 mRNA transcripts. As TTP inactivation causes accumulation of PD-L1 mRNA, interfering with the RAS pathway increases TTP binding to AU-rich elements of the transcripts, decreases PD-L1 protein production, and leads to enhanced antitumor immunity.

View the publication

Published in Immunity

Published

α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease

Protein aggregation drives neuronal death in Parkinson’s disease, although how transition of monomeric protein structures to aggregated forms causes toxicity is unknown. We demonstrate that aggregation of the protein α-synuclein generates beta sheet-rich oligomers, which localise to the mitochondrial inner membrane, where they impair complex I-dependent respiration, induce oxidation of ATP synthase and cause mitochondrial lipid peroxidation. These oxidation events result in opening of the permeability transition pore, triggering mitochondrial swelling, and ultimately cell death. This work highlights how structural conversion of a protein changes its physiological interaction with proteins and lipids, and induces pathology in human cell models of disease.

View the publication

Published in Nature Communications

Published

aPKC cycles between functionally distinct PAR protein assemblies to drive cell polarity

Through the use of aPKC inhibitors and genetic mutations, we demonstrate that aPKC cycles between distinct PAR-3 and CDC-42 dependent states, which define, respectively, the ability of the aPAR network to respond to spatial cues and to displace pPAR proteins from the membrane. We further show that cue sensing depends crucially on the oligomeric nature of the PAR-3 state, that the integrity of this cycle is required for coupling of cue-sensing and effector functions of the aPAR network, and that this cycle is enforced by activity of aPKC.

View the publication

Published in Developmental Cell

Published

Antioxidant role for lipid droplets in a stem cell niche of Drosophila

This paper is a continuation of our major research theme on how dividing stem cells in the CNS are able to resist environmental stresses that shut down proliferation in most other developing tissues. It reports the first identification, in any species, of lipid droplets as protectors of stem cells. We discovered that hypoxia induces lipid droplets in the neural stem cell niche and that these protect the neural stem cells themselves from damaging polyunsaturated fatty acid (PUFA) peroxidation reactions. This study laid the foundation for our current mechanistic studies into the antioxidant functions of lipid droplets during development and tumorigenesis.

View the publication

Published in Cell

Published

Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila

This reports the first identification, in any species, of the microbiome as a key mediator of developmental stress-induced longevity. We found that mild oxidative stress during development robustly increases lifespan via the selective elimination of Acetobacter from the microbiome. This study also highlights that targeted remodelling of the early-life microbiome can provide an efficient strategy for extending healthspan and lifespan.

View the publication

Published in Nature Communications

Published

A temporal window for signal activation dictates the dimensions of a nodal signaling domain

This paper shows how temporal information in the zebrafish embryo is transformed into a spatial pattern. We demonstrate how the Nodal signalling gradient is formed in the early zebrafish embryo and show that its size and shape are determined by a temporal signal activation window created by a microRNA-mediated delay in the translation of Lefty, a Nodal antagonist. This paper was important as it not only challenged the long-held view in the field that the Nodal gradient was formed by a reaction–diffusion mechanism, but highlighted the importance of signalling duration in gradient formation.

View the publication

Published in Developmental Cell

Published

Long-range signaling activation and local inhibition separate the mesoderm and endoderm lineages

The induction of endoderm and mesoderm by the signalling molecule Nodal has long been a textbook example of how a morphogen patterns vertebrate tissues. This study overturned the view that tissues are patterned through a single long-range morphogen gradient. Instead we demonstrated that Nodal functions in an incoherent feedforward loop with Fgf, to determine endoderm and mesoderm specification. Nodal induces long-range Fgf signaling, which is required for mesoderm induction, while simultaneously inducing a cell-autonomous Fgf signaling inhibitor within cells destined to become endoderm. This work represents a major step forward in deciphering the organising principles underlying early embryonic patterning.

View the publication

Published in Developmental Cell

Published