A5075947806- Ubiquitin and proteasome pathways
- Malaria Research and Control
- Microtubule and mitosis dynamics
- Genomics and Chromatin Dynamics
- Glycosylation and Glycoproteins Research
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Fungal and yeast genetics research
- Hippo pathway signaling and YAP/TAZ
- Complement system in diseases
- Advanced Proteomics Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- RNA and protein synthesis mechanisms
- DNA Repair Mechanisms
- Protein Degradation and Inhibitors
- Carbohydrate Chemistry and Synthesis
- COVID-19 and healthcare impacts
- Genetics and Neurodevelopmental Disorders
- COVID-19 Clinical Research Studies
- Mosquito-borne diseases and control
- Toxoplasma gondii Research Studies
- SARS-CoV-2 and COVID-19 Research
- Drug Transport and Resistance Mechanisms
- Invertebrate Immune Response Mechanisms
- Autophagy in Disease and Therapy
The Francis Crick Institute
2016-2025
Institute for Experimental Endocrinology and Oncology
2021
National Research Council
2021
University of Sheffield
2013
Jessop Hospital
2013
Cancer Research UK
2008-2012
GlaxoSmithKline (United Kingdom)
2005-2011
Molecular Discovery (United Kingdom)
2011
The Honourable Society of Lincoln's Inn
2008
Age UK
2006
Posttranslational modifications play key roles in regulating chromatin plasticity. Although various chromatin-remodeling enzymes have been described that respond to specific histone modifications, little is known about the role of poly[adenosine 5'-diphosphate (ADP)-ribose] remodeling. Here, we identify a enzyme, ALC1 (Amplified Liver Cancer 1, also as CHD1L), interacts with poly(ADP-ribose) and catalyzes PARP1-stimulated nucleosome sliding. Our results define DNA damage-response protein...
Replicated chromosomes are held together by the chromosomal cohesin complex from time of their synthesis in S phase onward. This requires replication fork–associated acetyl transferase Eco1, but Eco1's mechanism action is not known. We identified spontaneous suppressors thermosensitive eco1-1 allele budding yeast. An acetylation-mimicking mutation a conserved lysine cohesin's Smc3 subunit makes Eco1 dispensable for cell growth, and we show that acetylated an Eco1-dependent manner during DNA...
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part this mechanism occurs through lysine acetylation histone tails which are recognized by bromodomains. While the biological structural characterization many bromodomain containing proteins has advanced considerably, therapeutic tractability protein family is only now becoming understood. This paper describes discovery molecular potent (nM) small molecule inhibitors that...
S phase and mitotic onset are brought about by the action of multiple different cyclin-CDK complexes. However, it has been suggested that changes in total level CDK kinase activity, rather than substrate specificity, drive temporal ordering mitosis. Here, we present a phosphoproteomics-based systems analysis substrates fission yeast demonstrate phosphorylation can be temporally ordered during cell cycle single cyclin-CDK. This is achieved rising activity differential sensitivity to over wide...
The function of many DNA metabolism proteins depends on their ability to coordinate an iron-sulfur (Fe-S) cluster. Biogenesis Fe-S is a multistep process that takes place in mitochondria and the cytoplasm, but how it linked nuclear not known. Here, we demonstrate MMS19 forms complex with cytoplasmic assembly (CIA) CIAO1, IOP1, MIP18. Cytoplasmic also binds multiple involved metabolism. In absence MMS19, failure transfer clusters target associated protein instability preimplantation death...
Despite key roles in sister chromatid cohesion and chromosome organization, the mechanism by which cohesin rings are loaded onto DNA is still unknown. Here we combine biochemical approaches cryoelectron microscopy (cryo-EM) to visualize a loading intermediate locked between two gates that lead into ring. Building on this structural framework, design experiments establish order of events during loading. In an initial step, traverses N-terminal kleisin gate first opened upon ATP binding then...
Abstract DNA and histone modifications combine into characteristic patterns that demarcate functional regions of the genome 1,2 . While many ‘readers’ individual have been described 3–5 , how chromatin states comprising composite modification signatures, variants internucleosomal linker are interpreted is a major open question. Here we use multidimensional proteomics strategy to systematically examine interaction around 2,000 nuclear proteins with over 80 modified dinucleosomes representing...
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology the result third copy one or more approximately 230 genes on Hsa21, but identity causative dosage–sensitive and hence mechanisms underlying this remain unclear. Here, we show hearts from fetuses with embryonic Dp1Tyb mouse model reduced expression mitochondrial respiration cell...
Cyclic AMP (cAMP) is an important signalling molecule across evolution, but its role in malaria parasites poorly understood. We have investigated the of cAMP asexual blood stage development Plasmodium falciparum through conditional disruption adenylyl cyclase beta (ACβ) and downstream effector, cAMP-dependent protein kinase (PKA). show that both production activity PKA are critical for erythrocyte invasion, whilst key developmental steps precede invasion still take place absence signalling....
Highlights•Global analysis of phosphorylation dynamics during the fission yeast cell cycle•Reveals kinase-specific waves throughout interphase and mitosis•Mitotic kinases show significantly different dependencies on upstream CDK activity•Kinases directly downstream mediate earlier mitotic phosphorylationSummaryMultiple protein regulate cell-cycle progression, which cyclin-dependent (CDKs) are thought to act as master regulators. We have used quantitative phosphoproteomics analyze cycle at...
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling clinical annotation. Of 357 patients cancer, 118 were SARS-CoV-2 positive, 94 symptomatic 2 died of COVID-19. In this cohort, 83% had S1-reactive antibodies 82% neutralizing against wild type SARS-CoV-2, whereas antibody titers Alpha, Beta Delta variants substantially reduced. levels decreased in 13% patients, remained stable for up to...
Significance Most human secreted and cell surface proteins are modified by Ser/Thr(O)-linked glycosylation with N -acetylgalactosamine (O-GalNAc). While of fundamental importance in health disease, O-GalNAcglycosylation is technically challenging to study because a lack specific tools for biological assays. Here, we design an O-GalNAc–specific reporter molecule termed uridine diphosphate (UDP)– -( S )-azidopropionylgalactosamine (GalNAzMe) selectively label O-GalNAc glycoproteins living...
A membrane protein interacts with PKG and regulates calcium signals at multiple lifecycle stages in malaria parasites.
Abstract PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved adaptive age-related pathways. The carboxyl-terminus encodes serine/arginine-rich (RS) region an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over past 20 years. Here, we show that RS domain human directly interacts with nuclear export receptor NXF1. Inducible depletion...
The protozoan pathogen responsible for the most severe form of human malaria, Plasmodium falciparum, replicates asexually in erythrocytes within a membrane-bound parasitophorous vacuole (PV). Following each round intracellular growth, PV membrane (PVM) and host cell rupture to release infectious merozoites protease-dependent process called egress. Previous work has shown that, just prior egress, an essential, subtilisin-like parasite protease PfSUB1 is discharged into lumen, where it...
The R2TP cochaperone complex plays a critical role in the assembly of multisubunit machines, including small nucleolar ribonucleoproteins (snoRNPs), RNA polymerase II, and mTORC1 SMG1 kinase complexes, but molecular basis substrate recognition remains unclear. Here, we describe phosphopeptide binding domain (PIH-N) PIH1D1 subunit that preferentially binds to highly acidic phosphorylated proteins. A cocrystal structure PIH-N domain/TEL2 reveals specific mechanism which Lys57 64 PIH1D1, along...
The myocardin-related transcription factors (MRTF-A and MRTF-B) regulate cytoskeletal genes through their partner factor SRF. MRTFs bind G-actin, signal-regulated changes in cellular G-actin concentration control nuclear accumulation. also undergo Rho- ERK-dependent phosphorylation, but the function of MRTF elements signals involved MRTF-A export are largely unexplored. We show that Rho-dependent phosphorylation reflects relief from an inhibitory actin. map multiple sites serum-induced most...
Highlights•Pole4−/− mice exhibit impaired development and defective lymphocyte maturation•Pole4 is crucial for maintaining the stability of Polε complex•Polε hypomorphy causes replication stress via inefficient origin activation•p53 inactivation rescues all major developmental defects in Pole4-deficient miceSummaryDNA polymerase ε (POLE) a four-subunit complex leading strand eukaryotes. Budding yeast orthologs POLE3 POLE4 promote processivity vitro but are dispensable viability vivo. Here,...
Loss-of-function mutations in CDKL5 kinase cause severe neurodevelopmental delay and early-onset seizures. Identification of substrates is key to understanding its function. Using chemical genetics, we found that phosphorylates three microtubule-associated proteins: MAP1S, EB2 ARHGEF2, determined the phosphorylation sites. Substrate phosphorylations are greatly reduced knockout mice, verifying these as physiological substrates. In mouse neurons, dendritic microtubules have longer...
Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by serine/threonine kinase ULK and class III PI3 VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that loss significantly alters phosphoproteome, with novel high confidence substrates identified including complex member VPS15 AMPK subunit PRKAG2. We identify six ULK-dependent...