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.
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).
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.
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.
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.
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.
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.
Germinal center B cells recognize antigen through a specialized immune synapse architecture
Using new high-throughput imaging designed for rare cell subsets, we revealed that germinal centre B cells form uniquely patterned immune synapses to bind antigens. The separation of antigen into small clusters, along with specific cytoskeletal organisation results in enhanced mechanical forces transferred onto the B cell receptor-antigen bonds, increasing the mechanical affinity-discrimination power of germinal centre B cells compared to other B cell subsets. The work implicated germinal centre B cell mechanics in selection of high-affinity B cell clones in antibody responses and introduced novel DNA nanosensors for measuring cellular forces.
WNK1 kinase balances T cell adhesion versus migration in vivo
In this study we identified the WNK1 kinase as a negative regulator of CD4+ T cell adhesion and a positive regulator of T cell migration. Furthermore, we showed that WNK1 controls migration through the OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter. This was an unexpected finding since WNK1 had been previously shown to regulate salt homeostasis in the kidney. Our study is the first to have implicated movement of Na+, K+ and Cl- ions in the regulation of T cell migration.
Isoform diversity in the Arp2/3 complex determines actin filament dynamics
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.
Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-ᴅ-glucose positron emission and computed tomography
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.