A5012042682- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- DNA Repair Mechanisms
- Genetic Neurodegenerative Diseases
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Protein Degradation and Inhibitors
- Viral-associated cancers and disorders
- Genomics and Chromatin Dynamics
- Cancer-related Molecular Pathways
- interferon and immune responses
- Histone Deacetylase Inhibitors Research
- Neurological diseases and metabolism
- Peroxisome Proliferator-Activated Receptors
- Neurobiology and Insect Physiology Research
- Peptidase Inhibition and Analysis
- Alzheimer's disease research and treatments
- HIV Research and Treatment
- Lymphoma Diagnosis and Treatment
- Retinoids in leukemia and cellular processes
- PARP inhibition in cancer therapy
- RNA Research and Splicing
- Natural Compounds in Disease Treatment
- Click Chemistry and Applications
Karolinska Institutet
2014-2024
Nobel Foundation
2007-2023
Institute of Molecular and Cell Biology
2014
Science for Life Laboratory
2013
Uppsala University
2013
Leiden University Medical Center
2013
Latvian Biomedical Research and Study Centre
2002
Utrecht University
1996-1999
The Netherlands Cancer Institute
1993
VCP (VCP/p97) is a ubiquitously expressed member of the AAA+-ATPase family chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion, and ubiquitin-dependent protein degradation by proteasome. Mutations in cause multisystem degenerative disease consisting inclusion myopathy, Paget’s bone, frontotemporal dementia (IBMPFD). Here we show essential for autophagosome maturation. We generated cells stably expressing dual-tagged...
Protein degradation, chromatin remodeling, and membrane trafficking are critically regulated by ubiquitylation. The presence of several coexisting ubiquitin-dependent processes, each crucial importance to the cell, is remarkable. This brings up questions on how usage this versatile regulator negotiated between different cellular processes. During proteotoxic stress, accumulation ubiquitylated substrates coincides with depletion histone H2A remodeling. We show that redistribution ubiquitin...
Heterochromatin protein 1 (HP1) family members are chromatin-associated proteins involved in transcription, replication, and chromatin organization. We show that HP1 isoforms HP1-α, HP1-β, HP1-γ recruited to ultraviolet (UV)-induced DNA damage double-strand breaks (DSBs) human cells. This response requires the chromo shadow domain of is independent H3K9 trimethylation detect UV DSBs. Loss results high sensitivity light ionizing radiation nematode Caenorhabditis elegans, indicating essential...
Chromatin changes within the context of DNA repair remain largely obscure. Here we show that damage induces monoubiquitylation histone H2A in vicinity lesions. Ultraviolet (UV)-induced is dependent on functional nucleotide excision and occurs after incision damaged strand. The ubiquitin ligase Ring2 required for damage-induced ubiquitylation. UV-induced ubiquitylation signaling kinase ATR (ATM- Rad3-related) but not related ATM (ataxia telangiectasia-mutated). Although response coincides...
Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation protein deposits that contain components ubiquitin/proteasome system. Affected Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying 19–amino acid C-terminal extension generated transcriptional dinucleotide deletion. Here we show UBB+1 potent inhibitor ubiquitin-dependent proteolysis neuronal cells, and this inhibitory activity correlates with induction cell cycle arrest. Surprisingly,...
The presence of endoplasmic reticulum (ER) stress and impaired ubiquitin–proteasome system (UPS) activity has been independently implicated in the pathophysiology conformational diseases. Here, we reveal a link between ER functionality UPS. Treatment cells with different stressors delayed degradation an reporter substrate caused subtle but consistent accumulation three independent nuclear/cytosolic UPS substrates. A similar signature increase was observed upon induction transgenic mice...
The accumulation of protein deposits in neurons, vitro proteasome assays and over-expression studies suggest that impairment the ubiquitin–proteasome system (UPS) may be a common mechanism pathogenesis polyglutamine diseases such as Huntington disease spinocerebellar ataxias (SCAs). Using knock-in mouse model recapitulates clinical features human SCA7, including selective neuronal dysfunction, we assessed UPS at cellular resolution using transgenic mice express green fluorescent (GFP)-based...
Chromatin modifications are an important component of the DNA damage response (DDR) network that safeguard genomic integrity. Recently, we demonstrated nucleotide excision repair (NER)-dependent histone H2A ubiquitination at sites ultraviolet (UV)-induced damage. In this study, show a sustained damaged DNA, which requires dynamic by Ubc13 and RNF8. Depletion these enzymes causes UV hypersensitivity without affecting NER, is indicative function for RNF8 in downstream UV-DDR. targeted to...
In familial and sporadic amyotrophic lateral sclerosis (ALS) in rodent models of the disease, alterations ubiquitin-proteasome system (UPS) may be responsible for accumulation potentially harmful ubiquitinated proteins, leading to motor neuron death. spinal cord transgenic mice expressing ALS superoxide dismutase 1 (SOD1) gene mutation G93A (SOD1G93A), we found a decrease constitutive proteasome subunits during disease progression, as assessed by real-time PCR immunohistochemistry. parallel,...
Nucleotide excision repair (NER) is the principal pathway that removes helix-distorting deoxyribonucleic acid (DNA) damage from mammalian genome. Recognition of DNA lesions by xeroderma pigmentosum group C (XPC) protein in chromatin stimulated damaged DNA-binding 2 (DDB2), which part a CUL4A–RING ubiquitin ligase (CRL4) complex. In this paper, we report new function DDB2 modulating structure at lesions. We show elicits unfolding large-scale independently CRL4 Our data reveal marked adenosine...
The presence of intracellular ubiquitylated inclusions in neurodegenerative disorders and the role ubiquitin/proteasome system (UPS) degrading abnormal hazardous proteins have given rise to hypothesis that UPS-impairment underlies processes. However, this remains controversial for polyglutamine such as Huntington disease (HD). Whereas studies cellular models provided evidence favor attributable expression N-terminal fragment mutant huntingtin (N-mutHtt), similar on mouse failed do so....
The recognition of helix-distorting deoxyribonucleic acid (DNA) lesions by the global genome nucleotide excision repair subpathway is performed XPC–RAD23–CEN2 complex. Although it has been established that Rad23 homologs are essential to protect XPC from proteasomal degradation, unclear whether RAD23 proteins have a direct role in DNA damage. In this paper, we show association with ultraviolet-induced was impaired absence proteins. Furthermore, rapidly dissociated upon binding damaged DNA....
The cohesin complex, which is essential for sister chromatid cohesion and chromosome segregation, also inhibits resolution of intertwinings (SCIs) by the topoisomerase Top2. cohesin-related Smc5/6 complex (Smc5/6) instead accumulates on chromosomes after Top2 inactivation, known to lead a buildup unresolved SCIs. This suggests that can influence chromosomal association via its role in SCI protection. Using high-resolution ChIP-sequencing, we show localization budding yeast duplicated indeed...