A5021767059- PARP inhibition in cancer therapy
- Machine Learning in Materials Science
- X-ray Diffraction in Crystallography
- Mass Spectrometry Techniques and Applications
- Toxin Mechanisms and Immunotoxins
- DNA Repair Mechanisms
- Calcium signaling and nucleotide metabolism
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Integrated Circuits and Semiconductor Failure Analysis
- Electrostatic Discharge in Electronics
- Genomics and Phylogenetic Studies
- Microbial Natural Products and Biosynthesis
- Computational Drug Discovery Methods
- Nuclear Physics and Applications
- Ubiquitin and proteasome pathways
- Analytical Chemistry and Chromatography
- Cell death mechanisms and regulation
- Enzyme Structure and Function
- CRISPR and Genetic Engineering
- Sirtuins and Resveratrol in Medicine
- Genomics and Chromatin Dynamics
- Antibiotic Resistance in Bacteria
- Signaling Pathways in Disease
- Protein Degradation and Inhibitors
University of Oxford
2016-2025
Sir Robert McAlpine (United Kingdom)
2023
Max Planck Institute for Biology of Ageing
2014
Max Planck Society
2014
Cancer Research UK Manchester Institute
2009-2013
University of Manchester
2009-2013
Arcos (United States)
2011
Sophien-und Hufeland Klinikum
2011
Cancer Research UK
2006-2008
Rudjer Boskovic Institute
2000-2005
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...
The hyperthermophile Nanoarchaeum equitans is an obligate symbiont growing in coculture with the crenarchaeon Ignicoccus. Ribosomal protein and rRNA-based phylogenies place its branching point early archaeal lineage, representing new kingdom Nanoarchaeota. N. genome (490,885 base pairs) encodes machinery for information processing repair, but lacks genes lipid, cofactor, amino acid, or nucleotide biosyntheses. It smallest microbial sequenced to date, also one of most compact, 95% DNA...
ADP-ribosylation (ADPr) regulates important patho-physiological processes through its attachment to different amino acids in proteins. Recently, by precision mapping on all possible acid residues, we identified histone serine ADPr marks the DNA damage response. However, biochemical basis underlying this modification remained unknown. Here report that is strictly dependent PARylation factor 1 (HPF1), a recently regulator of PARP-1. Quantitative proteomics revealed does not occur cells lacking...
We report the identification of histone PARylation factor 1 (HPF1; also known as C4orf27) a regulator ADP-ribosylation signaling in DNA damage response. HPF1/C4orf27 forms robust protein complex with PARP-1 cells and is recruited to lesions PARP-1-dependent manner, but independently catalytic activity. Functionally, HPF1 promotes trans histones limits damage-induced hyper-automodification PARP-1. Human lacking exhibit sensitivity damaging agents PARP inhibition, thereby suggesting an...
ADP‐ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage viral infection is involved intra‐ extracellular signaling, chromatin transcriptional regulation, protein biosynthesis, cell death. ADP‐ribosylation catalyzed ADP‐ribosyltransferases (ARTs), which transfer ADP‐ribose from NAD + onto substrates. The modification, occurs as mono‐ or poly‐ADP‐ribosylation, reversible due...
ABSTRACT ADP-ribosylation is a common posttranslational modification that may have antiviral properties and impact innate immunity. To regulate this activity, macrodomain proteins enzymatically remove covalently attached ADP-ribose from protein targets. All members of the Coronavirinae , subfamily positive-sense RNA viruses, contain highly conserved within nonstructural 3 (nsp3). However, its function or targets during infection remain unknown. We identified several mutations greatly reduced...
Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADP-ribosylation (ADPr), reversible modification proteins regulates many different cellular processes. Several mammalian PARPs known to regulate the DNA damage response, but it is not clear which amino acids in primary ADPr targets. Previously, we reported ARH3 reverses newly discovered type (ADPr on serine residues; Ser-ADPr) and developed tools analyse this (Fontana et al., 2017). Here, show Ser-ADPr represents...
Deubiquitinating enzymes (DUBs) are important regulators of ubiquitin signaling. Here, we report the discovery deubiquitinating activity in ZUFSP/C6orf113. High-resolution crystal structures ZUFSP complex with reveal several distinctive features recognition and catalysis. Our analyses that is a novel DUB no homology to any known DUBs, leading us classify as seventh family. Intriguingly, minimal catalytic domain does not cleave polyubiquitin. We identify two binding domains ZUFSP: ZHA (ZUFSP...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising target because catalytic mutations render viruses nonpathogenic. Here, we report massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting active site of macrodomain. Crystallographic 2533 diverse fragments...
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors Mac1 have great therapeutic potential, at outset COVID-19 pandemic, there were no well-validated this nor, indeed, family, making target pharmacological orphan. Here, we report structure-based discovery development several different chemical scaffolds exhibiting...
Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in regulation many cellular pathways. Poly(ADP-ribose) (PAR) consists chains repeating ADP-ribose nucleotide units and synthesized by the family enzymes called poly(ADP-ribose) polymerases (PARPs). This can be removed hydrolytic action glycohydrolase (PARG) ADP-ribosylhydrolase 3 (ARH3). Hydrolytic activity macrodomain (MacroD1, MacroD2 TARG1) responsible for removal terminal unit complete reversion protein...