A5005057918- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- RNA regulation and disease
- Virus-based gene therapy research
- Cancer-related gene regulation
- Animal Genetics and Reproduction
- Pluripotent Stem Cells Research
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Glutathione Transferases and Polymorphisms
- CAR-T cell therapy research
- Innovation and Socioeconomic Development
- Cytokine Signaling Pathways and Interactions
- RNA Interference and Gene Delivery
- Cancer-related Molecular Pathways
- NF-κB Signaling Pathways
- RNA modifications and cancer
- Cytomegalovirus and herpesvirus research
- Phagocytosis and Immune Regulation
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- Thyroid Disorders and Treatments
- Cell death mechanisms and regulation
- interferon and immune responses
- Science, Research, and Medicine
- Biomedical Ethics and Regulation
AstraZeneca (Sweden)
2016-2025
Great Ormond Street Hospital
2024
University College London
2024
Austrian Academy of Sciences
2013-2020
Institute of Molecular Biotechnology
2013-2020
University of British Columbia
2019
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
2019
AstraZeneca (Brazil)
2018
AstraZeneca (United Kingdom)
2018
Institute for Experimental Endocrinology and Oncology
2003-2010
The Hace1-HECT E3 ligase is a tumor suppressor that ubiquitylates the activated GTP-bound form of Rho family GTPase Rac1, leading to Rac1 proteasomal degradation. Here we show that, in vertebrates, Hace1 targets for degradation when localized nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme. This event blocks de novo reactive oxygen species generation by Rac1-dependent NADPH oxidases, and thereby confers cellular protection from species-induced DNA damage cyclin...
Significance Oxidative stress is an important contributor to aging-associated diseases including cancer and neurodegeneration, antioxidant responses are critical limit manifestations of these diseases. We report that the tumor suppressor Homologous E6-AP Carboxyl Terminus domain Ankyrin repeat containing E3 ubiquitin–protein ligase 1 (HACE1) promotes activity transcription factor, nuclear factor erythroid 2-related 2 (NRF2), a master regulator antioxidative response. In Huntington disease...
The mutation patterns at Cas9 targeted sites contain unique information regarding the nuclease activity and repair mechanisms in mammalian cells. However, analytical framework for extracting such are lacking. Here, we present a novel computational platform called Rational InDel Meta-Analysis (RIMA) that enables an in-depth comprehensive analysis of Cas9-induced genetic alterations, especially InDels mutations. RIMA can be used to quantitate contribution classical microhomology-mediated end...
Abstract The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells animals. However, model generation for drug development is still expensive time-consuming, demanding more target flexibility faster turnaround times with high reproducibility. a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene its use targeted results functional integration into both human mouse culminating ODInCas9 mouse. Genomic can be performed various tissue...
Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates homeostasis, has recently emerged as an approach to reduce levels. The development humanized animal models important step validate and study human drug targets, use genome base editing been proposed mean target disease alleles. To address the lack validated test safety efficacy...
Pax genes encode for transcription factors essential tissue development in many species. Pax8, the only member of family expressed thyroid tissue, is involved morphogenesis gland and transcriptional regulation thyroid-specific genes. TTF-1, a homeodomain-containing factor, also has been demonstrated to play role gene expression. Despite presence Pax8 TTF-1 few other tissues, simultaneous expression two occurs thyroid, supporting idea that might cooperate influence In this report, we describe...
α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily lungs. In humans, AAT encoded by SERPINA1 (hSERPINA1) gene which point mutation (commonly referred to as PiZ) causes aggregation of miss-folded protein hepatocytes resulting subsequent damage. an attempt rescue pathologic phenotype mouse model human deficiency (AATD), we used adenovirus deliver Cas9 guide-RNA...
The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that is central gatekeeper of TNFR1-induced cell fate. Genetic inactivation inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance vivo. Moreover, TNF-induced apoptosis was impaired hace1 mutant cells knockout mice Mechanistically, essential for the ubiquitylation adaptor protein TRAF2 formation apoptotic caspase-8 effector complex. Intriguingly, loss...
Abstract Understanding how breaks form and are repaired in the genome depends on accurate measurement of frequency position DNA double strand (DSBs). This is crucial for identification a chemical’s damage potential safe development therapies, including editing technologies. Current DSB sequencing methods suffer from high background levels, inability to accurately measure low endogenous costs. Here we describe INDUCE-seq, which overcomes these problems, detecting simultaneously presence...
Cadherin (CDH)16/kidney-specific-cadherin was first described as a kidney-specific adhesion molecule and thereafter found expressed also in the thyroid gland. We show here that CDH16 fully colocalizes with CDH1/E-cadherin on basolateral plasma membrane of mouse human thyrocytes. In thyrocyte cultures, expression is dependent upon TSH, other differentiation markers. developing thyroid, at embryonic day 10.5, 1-2 d after main thyroid-specific transcription factors involved cell...
Lung cancer is the leading cause of deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung in women; however, underlying mechanisms remain unclear. Here we report that receptor activator nuclear factor-kB (RANK), key regulator osteoclastogenesis, frequently expressed primary tumors, an active RANK pathway correlates with decreased survival, and pharmacologic inhibition reduces tumor growth patient-derived xenografts. Clonal genetic inactivation KRasG12D...
We aim to characterize the causality and molecular functional underpinnings of HACE1 deficiency in a mouse model recessive neurodevelopmental syndrome called spastic paraplegia psychomotor retardation with or without seizures (SPPRS).By exome sequencing, we identified 2 novel homozygous truncating mutations 3 patients from families, p.Q209* p.R332*. Furthermore, performed detailed phenotypic analyses Hace1 knock-out (KO) mice SPPRS patient fibroblasts.We show that KO display many clinical...
HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of
Thyroid transcription factor gene 1 (TTF-1) is a homeobox-containing involved in thyroid organogenesis.During early development, the homeobox Nkx-2.5 expressed precursor cells coincident with appearance of TTF-1.The aim this study was to investigate molecular mechanisms underlying thyroid-specific expression.We show that C terminus interacts TTF-1 homeodomain and, moreover, expression dominant-negative isoform (N188K) reduces TTF-1-driven by titrating away from its target DNA.This process...
The molecular mechanisms leading to a fully differentiated thyrocite are still object of intense study even if it is well known that thyroglobulin, thyroperoxidase, NIS and TSHr the marker genes thyroid differentiation. It also Pax8, TTF-1, Foxe1 Hhex thyroid-enriched transcription factors responsible for expression above genes, thus phenotype. In particular, role Pax8 in developed gland was studied depth established plays key development However, date bases this factor have not been...
Among the approaches used to provide a functional inactivation of target protein, we have chosen recently described oligomerization chain reaction (OCR) strategy functionally inactivate transcription factor Pax8, member Pax gene family expressed in thyroid cells. The OCR is based on fusion self-associating coiled-coil (CC) domain nuclear promyelocytic leukemia (PML) proteins that are able self-associate naturally or form heterocomplexes. In tissue, Pax8 involved morphogenesis gland and...
The Pax gene family encodes transcription factors that are essential in organogenesis and the differentiation of various organs higher eukaryotes. proteins have a DNA binding domain at N-terminus, transcriptional activation C-terminus. How these domains interact with machinery cell is still unclear. In present paper, we describe identification by means immunological screening WW protein WBP-2 as biochemical interactor Pax8 (a protein-interaction containing two conserved tryptophan residues)....
<title>Abstract</title> Advances in designer DNA editors, such as programmable nucleases, PASTE, Prime, and base have recently proved their therapeutic value potential to treat genetic disorders. However, a comprehensive understanding of cellular activities is essential for improving editing efficiency ensuring safe clinical translation cell gene therapies. A myriad techniques emerged detect or anticipate genotoxic events, reflecting the increasing demand thorough characterisation over these...
CRISPR-Cas genome-editing nucleases hold substantial promise for human therapeutics 1–5 but identifying unwanted off-target mutations remains an important requirement clinical translation 6, 7 . For ex vivo therapeutic applications, previously published cell-based genome-wide methods provide potentially useful strategies to identify and quantify these mutation sites 8–12 However, a well-validated method that can reliably off-targets in has not been described date, leaving the question of...