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.
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.
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.
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.
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.
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.
Neutrophils support lung colonization of metastasis-initiating breast cancer cells
In this study we found that via the release of leukotrienes, neutrophils selectively support the more metastatic subset of cancer cells infiltrating the distant tissue and that this activity can be blocked by an inhibitor of leukotriene production. This is one of the most important publications from my laboratory, as it has contributed to the understanding of the crucial responses of neutrophils during metastatic progression.
Cyclooxygenase-dependent tumor growth through evasion of immunity
In this paper, we uncovered a potent mechanism of cancer immune evasion, namely cyclooxygenase (COX)-dependent secretion of prostaglandin E2 (PGE2) by tumour cells. We further showed that the growth of PGE2-secreting tumours in mice can be reversed by a combination of checkpoint blockade immunotherapy and COX inhibitors, suggesting that COX inhibition might be a useful addition to both conventional and immune-based therapy of cancer. This paper led to seven clinical trials worldwide to test combinations of prostaglandin E2 inhibition with checkpoint blockade cancer therapies.
DNA entry into and exit out of the cohesin ring by an interlocking gate mechanism
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.