Publication highlights

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Explore a selection of research cases studies from the past five years.

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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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SCAF4 and SCAF8, mRNA anti-terminator proteins

SCAF4 and SCAF8 were isolated in the mid-90s as proteins that bind the RNAPII C-terminal repeat domain (CTD) but little or nothing was known about their cellular function. This paper describes their function as the first eukaryotic mRNA anti-terminator proteins. Together, SCAF4 and SCAF8 coordinate the transition between elongation and termination, ensuring correct polyA site selection and RNAPII transcriptional termination in human cells.

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Published in Cell

Published

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

This TRACERx work shows that bespoke patient-specific panels to analyse ctDNA can be used to monitor MRD recurrence and tumour branched evolution in the adjuvant setting in the absence of macroscopic disease, and that tumour Ki67 index, necrosis, squamous histology and FDG-PET avidity are closely associated with ctDNA release. We further demonstrate the limitations of ctDNA approaches for early detection as a function of tumour volume and cancer cell number, and show that the subclone identified in ctDNA prior to disease recurrence is identical to the tumour subclone identified at metastatic sites, permitting adjuvant MRD studies to prevent recurrence.

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Published in Nature

Published

Tracking the evolution of non-small-cell lung cancer

This work evaluates the relationship between intratumour heterogeneity of single nucleotide variants and somatic copy number aberrations and recurrence free survival in non-small cell lung cancer. Diversity of chromosome number or structure rather than single nucleotide variants is associated with poorer recurrence free survival, independent of tumour stage in multivariable analyses. Through subclonal copy number analyses, mirrored subclonal allelic imbalance is found, driving parallel evolution of chromosome copy number gains or losses on either the maternal or paternal chromosome in different regions of the same tumour.

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Published in New England Journal of Medicine

Published

Allele-specific HLA loss and immune escape in lung cancer evolution

Through an analysis of TRACERx, extended from our haplotyping analysis, we developed an algorithm called LOHHLA which infers allele specific copy number aberrations in HLA. We find HLA loss occurs in 40% of early stage lung cancers, usually as a subclonal event, and is permissive for branched evolution associated with expansion of mutations predicted to bind the lost HLA allele.

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Published in Cell

Published

Neoantigen-directed immune escape in lung cancer evolution

We analysed the first 100 TRACERx patients to unravel how escape from adaptive immunity occurs in non-small cell lung cancer. Immune ‘hot’ tumours, characterised by a brisk lymphoid infiltrate, had been selected for HLA LOH or deleterious mutations in the antigen presentation machinery. In contrast immune ‘cold’ tumours with an absent lymphoid infiltrate had lost clonal neoantigens through DNA copy number loss events. We found evidence for negative selection of subclones early in tumour evolution harbouring neoantigens in genes essential for non-small cell lung cancer viability. Patient outcome was worse for tumours with evidence of an immune evasion event.

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Published in Nature

Published

B cell antigen extraction is regulated by physical properties of antigen-presenting cells

We demonstrated that mechanical forces and not enzymatic liberation are the physiological mechanism for acquisition of antigens by B cells from live presenting cells. Using DNA-based nanosensors we showed that B cell affinity discrimination is regulated by physical properties of the antigen-presenting cells and identified follicular dendritic cells as a stiff antigen presenting subset that promotes B cell affinity discrimination in germinal centres.

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Published in Journal of Cell Biology

Published

ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ

This paper represents an important step forward in our understanding of ATG9, the only multi-spanning autophagy protein and a major focus of my lab’s current work. Here we discovered the composition of the ATG9 vesicle and uncovered an important role for a protein which can induce membrane curvature and a lipid kinase. I chose this work as it has provided us with important insights into the function of ATG9A.

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Published in Journal of Cell Biology

Published

Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins

This paper follows on from our work on WAC and the role of centrosomes in autophagy. We discovered an important centriolar protein has a specific motif (LIR motif) enabling its binding to a key autophagy protein. In collaborative work, we determined the structure and the important features of the LIR motif, and extended the findings to a group of autophagy proteins to provide an important advance on our understanding of selective autophagy. I chose this work because it is a tour de force of structure and biochemistry and a very substantial collaboration between Structural Biology and Peptide Chemistry STPs

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Published in Nature Communications

Published

RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability

This paper shows that the ArhGAP9/12/15/27 and ArhGAP32/33 families of rhoGAPs are RPEL proteins whose activity is coupled to G-actin concentration. G-actin forms a 1:1 complex with these ArhGAPs, interacting with an RPEL motif located between the PH and GAP domains, thereby inhibiting their GAP activity. Mutations that block G-actin binding exhibit elevated GAP activity towards their substrate GTPases Rac and Cdc42. Strikingly, treatment of cells with drugs enhancing or inhibiting G-actin/ArhGAP interaction has corresponding effects on Rac GTP loading. These results establish a novel homeostatic feedback loop, in which ArhGAP12-family (and presumably ArhGAP32-family) GAP activity increases when G-actin levels become limiting.

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Published in Nature Cell Biology

Published

Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis

The first pan-tumour study to evaluate the contribution of fremashift mutations to generation of immunogenic peptides and anti-tumour immunity. Patent arising.

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Published in Lancet Oncology

Published

Fertile offspring from sterile sex chromosome trisomic mice

Here, we described a technique for reversing infertility in XXY (Klinefelter) and XYY (Jacob) syndrome mice. We showed that reprogramming of fibroblasts from these mice resulted in elimination of the extra sex chromosome, and that resulting XY cells could be converted by in vitro gametogenesis into functional sperm. Reprogramming could also chromosomally correct cells from Down syndrome mice and patients. The work revealed an unexpected role for reprogramming as a form of chromosome therapy.

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Published in Science

Published

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.

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Published in Cell

Published

Cell clustering promotes a metabolic switch that supports metastatic colonization

We show that the clustering of cancer cells following detachment from ECM results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis.

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Published in Cell Metabolism

Published

The SMX DNA repair tri-nuclease

First description of the SMX tri-nuclease that resolves recombination intermediates. Composed of SLX1-SLX4, MUS81-EME1 and XPF-ERCC1, the six-subunit complex was purified following baculovirus expression in insect cells. Characterization of the Holliday junction cleavage reaction revealed that the first incision was introduced by SLX1-SLX4, while the second was mediated by MUS81-EME1. We also found that MUS81-EME1 was activated by interaction with the SLX4 scaffold, ensuring that the second cut occurs in concert with SLX1-SLX4’s initial incision. The formation of SMX and activation of MUS81-EME1 provides a mechanistic basis for restriction of SMX activity to the later stages of the cell cycle.

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Published in Molecular Cell

Published

Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis

Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. This is the first vaccine against tuberculosis to be shown effective in humans since the advent of BCG in 1921. A product development and further testing plan has recently been agreed and we will contribute to the latter.

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Published in New England Journal of Medicine

Published