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

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Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor

A study led by the Blackman lab has shed new light on a key pathway that allows the malaria parasite to escape from the host’s red blood cells. Their findings identify a target that could be used to develop a new class of antimalarial drug designed to prevent disease progression.

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Published in The EMBO Journal

Published

TRF2-independent chromosome end protection during pluripotency

This work revealed that telomere protection is solved by distinct mechanisms in pluripotent and somatic tissues. In somatic cells, TRF2 sequesters the telomere within a t-loop, preventing telomere end-to-end fusions and inviability. In contrast, TRF2 is dispensable for telomere protection in pluripotent cells; ESCs lacking TRF2 grow normally, do not fuse their telomeres and form functional t-loops. Upon differentiation this unique attribute of stem cells is lost and TRF2 assumes its full role in end protection. The retention of end protection in the presence of t-loops, but absence of TRF2, confirmed that t-loops are a key mediator of telomere end protection irrespectively of how they form.

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Published in Nature

Published

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Memory B cells (MBCs) and plasma cells (PCs) are formed during the so-called germinal center (GC) B cell reaction. In the GC reaction B cells mutate their B cell receptor (BCR) genes and those that acquire a higher-affinity BCR for a pathogen antigen are presumably selected to survive and differentiate, whereas B cells carrying a lower-affinity BCR die. However, this cannot explain retention of GC B cells with varied BCR affinities and the formation of MBCs that normally carry lower-affinity BCRs. This work re-defines selection of GC B cells as permissive to ensure clonal diversity and broad protection.

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Published in Proceedings of the National Academy of Sciences of USA

Published

COVID-19 spike with biliverdin binding site.

SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity

A team led by the Cherepanov lab has found a molecule that can block the binding of a subset of human antibodies to SARS-CoV-2. This could explain patients who, despite having high levels of antibodies, become ill.

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Published in Science advances

Published

Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation

Here we showed that Sld3, which we previously identified as being one of two essential cyclin dependent kinase (CDK) substrates in replication, is a phosphopeptide binding protein which binds specifically to Mcm4 and Mcm6 when they have been phosphorylated by Dbf4 dependent kinase (DDK). Sld3 then directly recruits Cdc45 to MCM and, via CDK phosphorylation, recruits the remaining firing factors. We had previously shown that Sld3 is also one of two targets of the DNA damage checkpoint kinase involved in inhibiting origin firing in response to DNA damage. Thus, Sld3 plays key roles with all three kinases that regulate replication (CDK, DDK, Rad53).

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Published in EMBO Journal

Published

D614G SARS-CoV-2 variant spike protein

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Research from the Gamblin lab has compared the original SARS-CoV-2 spike protein with a mutated version which arose last spring. They have found structural differences that could help to explain why the mutated version remains the dominant form circulating in all recent variants of concern.

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Published in Proceedings of the National Academy of Sciences of USA

Published

Return to quiescence of mouse neural stem cells by degradation of a proactivation protein

This paper provided the first evidence that stem cells in the adult mouse hippocampus are heterogeneous in their behaviour, with most stem cells differentiating and leaving the niche after they have become active but a small fraction returning to a shallow state of quiescence. These “resting cells” have an essential role in the long-term maintenance of an active stem cell pool.

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Published in Science

Published

Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population

Stem cell numbers in the hippocampus of young adults stabilise due to coordinated changes in stem cell behaviour which ensures lifelong hippocampal neurogenesis, according to new research from the Guillemot lab.

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Published in Cell Stem Cell

Published

Epithelia use butyrophilin-like molecules to shape organ-specific γδ T cell compartments

This paper established that intestinal epithelial cells use BTNL/Btnl molecules to select for and regulate tissue-specific gamma delta T cell compartments. It established a biological mechanism by which epithelial cells communicate with local T cells at steady-state (“normality sensing”). Following on from our prototypic discovery of such a mechanism in mouse skin, the work established conservation of the process across tissues as well as across species. The system is unperturbed by microbial colonisation.

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Published in Cell

Published

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

Using a combination of structural biology, genome editing, and biochemistry, a new study from the Hill lab showed that Shprintzen–Goldberg syndrome is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, as previously predicted.

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Published in eLife

Published

SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice

Tumour development depends on cell intrinsic dysfunction, but extrinsic factors can also be important drivers. Deletion of p27, which is downregulated in many tumours, predominantly gives pituitary tumours in mice. Sox2, which is transcriptionally derepressed in the absence of P27, is also important for tumorigenesis in this and other systems. Using various approaches, we establish the regulatory interaction in vivo of SOX2 and p27 and show that SOX2 is required independently, both cell-autonomously in the endocrine cells that form the tumours and non-cell-autonomously, in adjacent pituitary stem cells, to orchestrate tumorigenesis in the absence of P27.

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Published in Proceedings of the National Academy of Sciences of USA

Published

A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

New research from the McDonald lab combined crystallography and cryo-electron microscopy to reveal how the RET receptor, tyrosine kinase, recognises different GDNF family ligand/co-receptor pairs.

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Published in Structure

Published

Frequent loss-of-heterozygosity in CRISPR-Cas9–edited
early human embryos

Crick researchers, including Kathy Niakan and James Turner, have revealed that CRISPR-Cas9 genome editing can lead to unintended mutations at the targeted section of DNA in early human embryos. The work highlights the need for greater awareness of and further research into the effects of CRISPR-Cas9 genome editing, especially when used to edit human DNA in laboratory research.

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Published in Proceedings of the National Academy of Sciences of USA

Published

CDK substrate phosphorylation and ordering the cell cycle

A phosphoproteomics analysis of CDK substrates has shown that the correct cell cycle temporal order of CDK substrate phosphorylation can be established by a single CDK. It is shown that there is a 50-fold increase of in vivo CDK activity during the cell cycle. Temporal order is achieved by a combination of this rise with differential sensitivity of substrates to CDK activity. Phosphosite turnover is very rapid which helps ensure sharp cell cycle transitions.

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Published in Cell

Published

Astrocytes

Reactive astrocytes in ALS display diminished intron retention

A study led by Rickie Patani has identified the trigger of a key cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neurone disease. The findings could help develop new treatments for many neurological diseases with the same change, including Parkinson’s and Alzheimer’s.

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Published in Nucleic Acids Research

Published

The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens

Immune cells such as type 1 conventional dendritic cells (cDC1) can “eat” (phagocytose) dead tumour or virally-infected cells and present associated antigens to CD8+ T cells to elicit a tumour- or virus-specific cytotoxic T cell response. How antigens from the debris get presented on MHC class I (MHC-I) molecules on cDC1 has long been puzzling as MHC-I normally presents antigens found in the cytosol. This paper shows that cDC1 use the DNGR-1 receptor to induce phagosomal rupture, releasing the debris-associated antigens into the cytosol. These findings have implications for our understanding and manipulation of immunity to infection and cancer.

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Published in Nature Immunology

Published

The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

This study showed that epigenetic mechanisms play an important role in generating functional heterogeneity within tumours, and can override genetic alterations that initiate the disease by inhibiting cell proliferative potential during tumour growth. The finding that heterogeneous patterns of H1.0 are broadly observed in cancer and that H1.0 is an independent predictor of patient survival in multiple types of solid tumours makes a strong case for a general role of epigenetic regulators in cancer. Mechanistic characterisation of how H1.0 controls malignant self-renewing states also provided insights into general mechanisms through which the linker histone regulates gene expression.

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Published in Science

Published

Disruption of the MSL complex inhibits tumour maintenance by exacerbating chromosomal instability

Research from the Scaffidi lab has developed a new strategy to identify cancer-specific vulnerabilities. They identified a group of proteins, called the male-specific lethal (MSL) acetyltransferase complex, which could be used to increase chromosomal instability in cancer cells without inducing severe adverse effects in normal tissues.

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Published in Nature Cell Biology

Published

The migratory pathways of the cells that form the endocardium, dorsal aortae, and head vasculature in the mouse embryo

Using recently developed live imaging techniques, the Smith lab has investigated the migration of cells that initially form the circulatory system in the mouse embryo. Their findings show that, contrary to previous understanding, the yolk sac and embryonic circulatory systems share common origins.

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Published in BMC developmental biology

Published

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

We investigated how intratumour heterogeneity affects response to checkpoint blockade and how cancers might be treated based on evolutionary principles. Durable clinical benefit to checkpoint blockade in lung cancer and melanoma was associated with a high burden of clonal neoantigens; in contrast, tumours that progressed early on therapy had a higher burden of heterogeneous neoantigens. We could predict clonal neoantigens present in every tumour cell and identify immune cells that recognise them, suggesting that development of adoptive T cell or vaccination strategies targeting such clonal neoantigens might limit therapeutic escape and resistance mechanisms.

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Published in Science

Published