Publication highlights

Fanconi Anemia is a devastating genetic disease characterised by genome instability, developmental defects, and cancer predisposition, involving defects in the FA DNA repair pathway. Central to the FA pathway is the FANCM protein, which acts as both a DNA damage sensor to modify another protein called FANCD2, and as a fascinating motor protein that “zips up” DNA. This report is the first comprehensive structural and mechanistic understanding of how FANCM recognises DNA damage and activates modification of the FANCD2 and FANCI proteins through a process called monoubiquitination. The paper reveals how FANCM evolved from being a DNA repair motor protein into a complex sensor coupling DNA damage recognition to selective pathway activation.

Hepatitis Delta Virus (HDV) is a serious infection that worsens liver disease in people who already are living with Hepatitis B. It is highly endemic in the World Health Organisation (WHO) African region, where unique forms of the virus exist and the need for treatment is especially urgent. Novel drugs to cure this disease are being trialed. The researchers looked at all HDV clinical trials registered globally. Out of 47 trials, most were based in WHO Europe (about 7 out of 10), with some in the Americas and Western Pacific regions. Shockingly, none of the trials took place in the WHO African region. They believe clinical trials in WHO Africa are essential to make sure that new drugs work for people across different populations and virus types, and to ensure fair access when these treatments become available.

Researchers at the Francis Crick Institute have developed a new stem cell model of the mature human amniotic sac, which replicates development of the tissues supporting the embryo from two to four weeks after fertilisation. The new 3D model – called a post-gastrulation amnioid (PGA) – closely resembles the human amnion and other supportive tissues after gastrulation. The team developed PGAs by culturing human embryonic stem cells in a series of steps with just two chemical signals over 48 hours, after which the cells organised themselves into the inner and outer layers of the amnion. A sac-like structure formed by day 10 in over 90% of the PGAs, which expanded in size over 90 days. The researchers showed that a transcription factor called GATA3 is necessary to kick-start amnion development and that signals from the amnion can communicate with embryonic cells to stimulate growth. Finally, they believe PGAs could also provide an alternative source of amniotic membranes for medical procedures like cornea reconstruction.

Researchers at the Francis Crick Institute have revealed insight into why embryos erase a key epigenetic mark during early development, suggesting this may have evolved to help form a placenta. The team at the Crick investigated, for the first time, epigenetic changes in embryos of a marsupial, which diverged from eutherian mammals 160 million years ago. They created a map of DNA methylation in opossum eggs, sperm and embryos, finding that levels of methylation in eggs and sperm were more similar to each other than they were in eutherians. However, unlike eutherians, opossum embryos did not undergo a full wiping event. Instead, DNA methylation was retained in the early embryo, with loss occurring much later, and DNA demethylation was largely restricted to a specific supportive tissue called the trophectoderm, which becomes the marsupial placenta. These findings show that demethylation isn’t universally required for formation of an early mammalian embryo, instead, based on their findings, the team believe that wiping may have evolved specifically for the development of the placenta.

Researchers at UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

The Salmonella protein SteE forcibly reprogrammes the eukaryotic kinase GSK3 so it acts on a new set of substrates that benefit Salmonella virulence. Kinase reprogramming depends on several short linear motifs in SteE that trick GSK3 into recognising SteE as a 'normal' cellular signalling partner. Researchers at the Crick have shown how each motif contributes to manipulating GSK3, and revealed the existence of SteE-like proteins in other bacterial pathogens. This work will aid the rational design of synthetic reprogramming proteins.

The initiation of DNA replication occurs at tens of thousands of sites on the human genome during every S phase, but in the absence of any consensus DNA sequence, it is unclear how these sites are specified. Researchers at the University of Cambridge and the Crick identified sites with increased density during quiescence and G1 phase that overlap with DNA replication origins. The increased density derives from changes made by enzymes at these sites, and inhibition of these enzymes reversibly prevented DNA replication and cell proliferation. These findings provide a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites, and for the once-per-cell cycle control of origin activation.

Researchers at the Crick and the University of York with clinicians from Great Ormond Street and Guy’s and St Thomas’ Hospitals have investigated all the kinase enzymes expressed (the kinome) in children with a disease called Multiple Endocrine Neoplasia Type 2 (MEN2), to identify new therapeutic markers and targets. This autosomal dominant disease leads to several cancers including the development of thyroid cancer and is caused by pathogenic variants in the receptor tyrosine kinase RET. But the development and progression of these tumours are not always predictable, even within families with the same RET pathogenic variant. This study identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, each of which were subsequently validated in patient thyroid tissue.

Researchers have shown that the Cryptosporidium parasite exports a protein into infected intestinal cells, altering the gut environment and enabling the parasite to survive and replicate. They investigated a major protein in a family of exported proteins, called microvilli protein 1 (MVP1), finding that, within the epithelial cell, it interacts with human proteins that are responsible for maintaining structure and regulating cellular projections like microvilli. One of the proteins that MVP1 interacts with, called EBP50, is crucial for stabilising pumps on the surface of the cells that bring salts in. Disrupting these pumps results in diarrhoea, so the team believes that MVP1 might be one of the key factors that drive the symptoms caused by Cryptosporidium. They also found that MVP1 interacts with the same structural proteins as the Map protein, exported by the E. Coli bacteria, which also causes microvilli elongation.

Researchers at the Crick and UCL Queen Square Institute of Neurology have shown that alpha-synuclein, the protein that aggregates in Parkinson’s disease, can trigger widespread RNA editing in astrocytes as part of an anti-viral innate immune response. They used human stem cells to generate astrocytes, the most abundant cell type in the brain. Using molecular biology, genomic and computational approaches, they showed that forms of alpha-synuclein trigger the same innate immune pathways in astrocytes that viruses do. One consequence of this response was a marked increase in RNA editing, with extensive changes throughout the genetic code as it is converted into proteins.