A5062998210- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- interferon and immune responses
- Toxin Mechanisms and Immunotoxins
- Machine Learning in Bioinformatics
- Cell Image Analysis Techniques
- Electrostatic Discharge in Electronics
- Integrated Circuits and Semiconductor Failure Analysis
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Microtubule and mitosis dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Hydrocarbon exploration and reservoir analysis
- Genetics and Neurodevelopmental Disorders
- Lipid metabolism and biosynthesis
- Hepatocellular Carcinoma Treatment and Prognosis
- Computational Drug Discovery Methods
- Pediatric health and respiratory diseases
- Trauma Management and Diagnosis
- Endoplasmic Reticulum Stress and Disease
University of Oxford
2020-2024
Huashan Hospital
2016-2024
Fudan University
2016-2024
East China Normal University
2024
State Key Laboratory of Medical Neurobiology
2023-2024
Third Affiliated Hospital of Sun Yat-sen University
2010
Sun Yat-sen University
2010
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...
Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain lesions. ALC1/CHD1L nucleosome-remodeling enzyme that responds damage, but its precise function in repair remains unknown. Here we report loss ALC1 confers sensitivity PARP inhibitors, methyl-methanesulfonate, uracil misincorporation, which reflects the need remodel nucleosomes following base excision by glycosylases prior handover APEX1. Using CRISPR screens, establish synthetic lethal with...
ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions vivo remain unclear. ARH3 is only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but much less efficient than against poly(ADP-ribose) (PAR) chains vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout cell cycle, including mitosis, surprisingly well tolerated. Conversely, persistent PARylation highly...
Abstract Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, target residues PARP1-mediated ADP-ribosylation remain ambiguous. To explicate regulome, we analyze human cells depleted for key regulators PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, characterize 1,596 sites, displaying up to 1000-fold regulation across investigated knockout cells. We find that HPF1 ARH3...
Ubiquitylation had been considered limited to protein lysine residues, but other substrates have recently emerged. Here, we show that DELTEX E3 ligases specifically target the 3′ hydroxyl of adenosine diphosphate (ADP)–ribosyl moiety can be linked a protein, thus generating hybrid ADP-ribosyl-ubiquitin modification. Unlike known hydroxyl-specific E3s, which proceed via covalent E3~ubiqutin intermediate, enzymes are RING E3s stimulate direct ubiquitin transfer from E2~ubiquitin onto...
PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little known about ADP-ribosylation activity PARP14, including its substrate specificity or how PARP14-dependent reversed. We show that dual-function enzyme with both ADP-ribosyl hydrolase acting on protein nucleic acid substrates. In particular, we macrodomain 1 an active hydrolase. also demonstrate hydrolytic for first PARP9. reveal expression mutant...
AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 models 17 canonical members human PARP family supplemented this analysis with new experiments an overview recent published data. proteins are typically involved in modification nucleic acids mono or poly(ADP-ribosyl)ation, but function can be modulated by presence various auxiliary domains. Our...
Abstract Although ubiquitylation had traditionally been considered limited to proteins, the discovery of non-proteinaceous substrates (e.g. lipopolysaccharides and adenosine diphosphate ribose (ADPr)) challenged this perspective. Our recent study showed that DTX2 E3 ligase efficiently ubiquitylates ADPr. Here, we show ADPr activity is also present in another DELTEX family member, DTX3L, analysed both as an isolated catalytic fragment full-length PARP9:DTX3L complex, suggesting it a general...
Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome–related protein Spartin activates recruits HECT-type E3 Itch to droplets (LDs) regulate their turnover. this study, we find that promotes formation condensates independent LDs. through its multiple PPAY-motif platform generated by...
Structurally complex genomic regions, such as centromeres, are inherently difficult to duplicate. The mechanism behind centromere inheritance is not well understood, and one of the key questions relates reassembly centromeric chromatin following DNA replication. Here, we define ERCC6L2 a regulator this process. accumulates at centromeres promotes deposition core factors. Interestingly, ERCC6L2−/− cells show unrestrained replication DNA, likely caused by erosion chromatin. Beyond facilitates...
The recent discovery of non-proteinaceous ubiquitylation substrates broadened our understanding this modification beyond conventional protein targets. However, the existence additional types remains elusive. Here, we present evidence that nucleic acids can also be directly ubiquitylated via ester bond formation. DTX3L, a member DELTEX family E3 ubiquitin ligases, ubiquitylates DNA and RNA in vitro activity is shared with DTX3, but not other members DTX1, DTX2 DTX4. DTX3L shows preference for...
Background: The aim of this study was to evaluate the therapeutic effect autogenous semitendinosus graft and endobutton technique, compare with hook plate in treatment Rockwood type III acromioclavicular (AC) joint dislocation. Methods: From April 2012 2013, we treated 46 patients AC Patients were randomly divided into two groups: Group A using a B technique. All participants followed up for 12 months. Radiographic examinations performed every 2 months postoperatively, clinical evaluation...
ABSTRACT The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising target because catalytic mutations render viruses non-pathogenic. Here, we report massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting active site of macrodomain. Crystallographic diverse fragment libraries resulted in 214 unique macrodomain-binding...
Abstract PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription and DNA replication stress management. However, little known about ADP-ribosylation activity PARP14, including its substrate specificity or how PARP14-dependent reversed. Here we show that dual function enzyme with both ADP-ribosyl hydrolase acting on protein nucleic acid substrates. In particular, macrodomain 1 an active hydrolase. We also demonstrate hydrolytic for first PARP9. reveal...
Abstract Recent discoveries expanding the spectrum of ubiquitylation substrates to include non-proteinaceous molecules have broadened our understanding this modification beyond conventional protein targets. However, existence additional types remains elusive. Here, we present evidence that nucleic acids can also be directly ubiquitylated. DTX3L, a member DELTEX family E3 ubiquitin ligases, ubiquitylates DNA and RNA in vitro activity is not shared with another DTX2. DTX3L shows preference for...
Structures from the Stone Age can provide unique insights into Late Glacial and Mesolithic cultures around Baltic Sea. Such structures, however, usually did not survive within densely populated Central European subcontinent. Here, we ...The Sea basins, some of which only submerged in mid-Holocene, preserve structures that on land. Yet, discovery these features is challenging requires cross-disciplinary approaches between archeology ...