A5030906128- DNA Repair Mechanisms
- Nuclear Receptors and Signaling
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- PARP inhibition in cancer therapy
- RNA Research and Splicing
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Virus-based gene therapy research
- NF-κB Signaling Pathways
- Immune Cell Function and Interaction
- Circular RNAs in diseases
- Congenital heart defects research
- Cancer therapeutics and mechanisms
- Microbial Metabolic Engineering and Bioproduction
- Cell death mechanisms and regulation
- Adipose Tissue and Metabolism
- Macrophage Migration Inhibitory Factor
- Estrogen and related hormone effects
- Engineering Diagnostics and Reliability
- Inflammasome and immune disorders
- Organic Chemistry Cycloaddition Reactions
- Endoplasmic Reticulum Stress and Disease
- Cytokine Signaling Pathways and Interactions
- Genetics and Neurodevelopmental Disorders
MRC Toxicology Unit
2015-2019
Medical Research Council
2015-2019
University of Cambridge
2019
University of Leicester
2014-2017
Ludwig Cancer Research
2004-2011
Karolinska Institutet
2006
Structure Fédérative de Recherche Biosciences
2006
Ludwig Cancer Research
2006
École Normale Supérieure de Lyon
2006
Centre National de la Recherche Scientifique
2006
The progression of neurogenesis relies on proneural basic helix–loop–helix (bHLH) transcription factors. These factors operate in undifferentiated neural stem cells and induce cell cycle exit the initiation a neurogenic program. However, transient expression bHLH proteins progenitors indicates that neuronal traits must rely previously unexplored mechanisms operating downstream from proteins. Here we show HMG-box Sox4 Sox11 are critical importance, proteins, for establishment pan-neuronal...
Abstract The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution damage but mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha Dicer, control recruitment factors from multiple pathways to sites damage. Depletion significantly reduces by both homologous recombination (HR) non-homologous end joining (NHEJ). required within minutes break induction,...
Repair of double-stranded DNA breaks (DSBs) in mammalian cells primarily occurs by the non-homologous end-joining (NHEJ) pathway, which requires seven core proteins (Ku70/Ku86, DNA-PKcs (DNA-dependent protein kinase catalytic subunit), Artemis, XRCC4-like factor (XLF), XRCC4 and ligase IV). Here we show using combined affinity purification mass spectrometry that co-purifies with all known NHEJ factors. Furthermore, have identified a novel evolutionary conserved associated DNA-PKcs-c9orf142....
The preservation of a pool neural precursors is prerequisite for proper establishment and maintenance functional central nervous system (CNS). Both Notch signaling SoxB1 transcription factors have been ascribed key roles during this process, but whether these use common or distinct mechanisms to control progenitor unsettled. Here, we report that the capacity maintain cells in an undifferentiated state requires activity proteins, whereas mechanism by which block neurogenesis independent...
DNA-dependent protein kinase (DNA-PK) is a central regulator of DNA double-strand break (DSB) repair; however, the identity relevant DNA-PK substrates has remained elusive. NR4A nuclear orphan receptors function as sequence-specific DNA-binding transcription factors that participate in adaptive and stress-related cell responses. We show here proteins interact with catalytic subunit and, upon exposure to damage, translocate DSB foci by mechanism requiring activity poly(ADP-ribose)...
Significance High-risk neuroblastomas (NBs) show undifferentiated/poorly differentiated morphology as a distinctive feature. We have identified the transcription factor ZNF281 that can counteract neuronal differentiation of primary neurons in culture and NB cells. The expression is inhibited by TAp73 promoted MYCN. In turn, inhibits GDNF NRP2, two proteins associated with differentiation. patients NB, higher high-risk worse prognosis. Understanding molecular mechanisms regulate relevant for...
PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms action remain largely unclear. Here we characterise interactomes and its paralogs, XLF XRCC4, to show that these factors share ability interact with polymerase λ (Pol λ), stimulate activity are required for recruitment Pol laser-induced damage sites. Stimulation by XRCC4 paralogs requires direct interaction between SP/8 kDa domain their N-terminal head domains...
Efficient repair of DNA double-strand breaks (DSBs) is critical importance for cell survival. Although non-homologous end joining (NHEJ) the most used DSBs pathway in cells, how NHEJ factors are sequentially recruited to damaged chromatin remains unclear. Here, we identify a novel role zinc-finger protein ZNF281 participating ordered recruitment factor XRCC4 at damage sites. lesions within seconds after through mechanism dependent on its binding domain and, least part, poly-ADP ribose...
The recently solved crystal structure of the orphan nuclear receptor (NR) Nurr1 ligand-binding domain (LBD) showed that lacks a cavity for ligand binding and canonical NR co-activator-binding site. Computer modeling LBD identified hydrophobic region on surface was positioned opposite side from classical Site-directed mutagenesis demonstrated this is critical activity LBD. Most mutations introduced in reduced or abolished transcriptional LBD, but mutation at lysine (K577) resulted drastically...
Activation-induced cell death (AICD), a term originally coined for the anti-CD3-induced apoptosis of T hybridomas and thymocytes, is predominantly driven by receptors has been involved in control autoreactive cells periphery. In Do-11.10 hybridoma model AICD, activation receptor (TCR) results Fas-dependent apoptosis. Here, we show that inhibition transcription factor nuclear κB (NFκB) resulted increased sensitivity to TCR-mediated apoptosis, correlating with defective induction...
Although poly-ADP-ribosylation (PARylation) of DNA repair factors had been well documented, its role in the double-strand breaks (DSBs) is poorly understood. NR4A nuclear orphan receptors were previously linked to DSB repair; however, their function process remains elusive. Classically, NR4As as transcription using a specialized tandem zinc-finger DNA-binding domain (DBD) for target gene induction. Here, we show that DBD bi-functional and can bind poly-ADP-ribose (PAR) through pocket...
The Fas ligand (FasL)/Fas pathway is crucial for the maintenance of homeostasis peripheral immune system. Its importance illustrated by spontaneous mouse mutants gld andlpr which lack functional FasL and receptor, respectively. These animals develop lymphadenopathy, splenomegaly, increased serum Ig autoantibodies, leading to an autoimmune syndromeand premature death. Rel/NF-κB family transcription factors plays important role in lymphocyte proliferation survival. In this report, we studied...
Göttingen Minipigs show several anatomical, physiological, and pathogenetical similarities to humans serve an important role in translational studies for example as large animal models of disease. In recent years, the number transgenic has increased, advanced genetic techniques simplify generation animals with precisely tailored modifications. These modifications are designed replicate alterations responsible human addition serving valuable disease models, also considered promising donors...
Common hallmarks of cancer include the dysregulation cell cycle progression and acquisition genome instability. In tumors, G1 checkpoint induction is often lost. This increases reliance on a functional G2/M to prevent through mitosis with damaged DNA, avoiding introduction potentially aberrant genetic alterations. Treatment tumors ionizing radiation (IR) utilizes this dependence checkpoint. Therefore, identification factors which regulate process could yield important biomarkers for refining...