A5074467963- DNA Repair Mechanisms
- Telomeres, Telomerase, and Senescence
- CRISPR and Genetic Engineering
- Mitochondrial Function and Pathology
- Cancer therapeutics and mechanisms
- Cancer, Hypoxia, and Metabolism
- PARP inhibition in cancer therapy
- RNA modifications and cancer
- Cytomegalovirus and herpesvirus research
- Carcinogens and Genotoxicity Assessment
- Cancer-related Molecular Pathways
- bioluminescence and chemiluminescence research
- Genetics, Aging, and Longevity in Model Organisms
- DNA and Nucleic Acid Chemistry
- Bioactive Compounds and Antitumor Agents
- ATP Synthase and ATPases Research
- Photosynthetic Processes and Mechanisms
- Oral and Maxillofacial Pathology
- Polyomavirus and related diseases
- Molecular Biology Techniques and Applications
- Metal-Catalyzed Oxygenation Mechanisms
- RNA Interference and Gene Delivery
- Genomics, phytochemicals, and oxidative stress
- Biochemical and Molecular Research
- Advanced biosensing and bioanalysis techniques
Karolinska Institutet
2018-2025
Science for Life Laboratory
2018-2025
Centro de Investigación Biomédica en Red
2022-2025
Instituto de Investigaciones Biomédicas Sols-Morreale
2022-2024
Universidad Autónoma de Madrid
2022-2024
Centre for Biomedical Network Research on Rare Diseases
2022-2024
Instituto de Investigación de Enfermedades Raras
2024
Spanish National Cancer Research Centre
2014-2019
Centro de Investigación del Cáncer
2014-2017
The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG because Ogg1-deficient mice are resistant acute systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention treatment inflammation. We developed TH5487, selective active-site inhibitor OGG1, which hampers binding repair well tolerated by...
Abstract Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis unknown. Here we show, by whole-exome sequencing of TP53 -negative Li–Fraumeni-like (LFL) family including CAS cases, that missense variant (p.R117C) in POT1 ( protection telomeres 1 ) gene responsible for CAS. The same alteration found two other LFL families with CAS, supporting the causal effect identified mutation. We extend analysis to no and find mutation breast AS family. recently once 121,324 studied...
Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease (APE1) and initiating repair. Here, we describe small molecule (TH10785) that interacts with the phenylalanine-319 glycine-42 amino acids of OGG1, increases enzyme activity 10-fold, generates previously undescribed β,δ-lyase enzymatic function. TH10785 controls catalytic mediated nitrogen base within its molecular structure. In cells, OGG1...
: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with abasic (AP site) excision repair (BER) intermediate. Cleaving this reversible structure is rate-determining step in initiation of 8-oxoguanine (8-oxoG) for glycosylase 1 (OGG1). The OGG1 AP lyase activity can be increased using small molecule binders, called organocatalytic switches, cleave backbone similar manner as bifunctional glycosylase. In search novel switches we here identify...
Abstract Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target exploit reactive oxygen species (ROS) elevation cancer. Although depletion is well tolerated non-transformed cells, report here...
Cisplatin-based chemotherapy has associated clinical disadvantages, such as high toxicity and resistance. Thus, the development of new antitumor metallodrugs able to overcome different barriers is a public healthcare priority. Here, we studied mechanism action isomers trans cis-[PtI
The most common oxidative DNA lesion is 8-oxoguanine which mainly recognized and excised by the 8-oxoG glycosylase 1 (OGG1), initiating base excision repair (BER) pathway. Telomeres are particularly sensitive to stress (OS) disrupts telomere homeostasis triggering genome instability. In present study, we have investigated effects of inactivating BER in OS conditions, using a specific inhibitor OGG1 (TH5487). We found that TH5487 blocks initiation at telomeres causing an accumulation oxidized...
Abstract Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC correlates survival. All six cell lines investigated were dependent on NEIL3 catalytic activity for prevention of senescence, while was dispensable nontransformed cells. NEIL3-depleted accumulated oxidative DNA lesions specifically at telomeres, resulting telomere dysfunctional foci 53BP1...
PARP1 plays a critical role in the base excision repair (BER) pathway, and inhibition leads to specific cell death, through synthetic lethal interaction, context of BRCA1/2 deficiency. To date, up five different PARP inhibitors (PARPi), have been approved, nevertheless, acquisition resistance PARPi is common there increasing interest enhancing responses expand their use other tumour types.We hypothesized that BER members could be additional partners with mutated BRCA genes. test this, we...
// Carlos Benitez-Buelga 1 , Tereza Vaclová Sofia Ferreira Miguel Urioste 2, 5 Lucia Inglada-Perez 3, Nora Soberón 4 Maria A. Blasco Ana Osorio 1, Javier Benitez Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain 2 Familial Clinical Unit, 3 Endocrine Telomere and Telomerase Network on Rare Diseases (CIBERER), Correspondence to: Benitez, e-mail: jbenitez@cnio.es Keywords: BRCA1 BRCA2, telomere shortening, OGG1 polymorfism, cancer risk modifier, DNA...
// Carlos Benítez-Buelga 1 , Juan Miguel Baquero Tereza Vaclova Victoria Fernández Paloma Martín 1, 4 Lucia Inglada-Perez 2, Urioste 3, Ana Osorio and Javier Benítez Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 2 Endocrine 3 Familial Unit, Network on Rare Diseases (CIBERER), Correspondence to: Benítez, email: jbenítez@cnio.es Keywords: BRCA1 BRCA2; NEIL2 polymorphism cancer risk modifier; mRNA levels; oxidative DNA damage Received: March 28, 2017...
Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known telomeropathies. These characterized by premature shortening, increased DNA damage oxidative stress. Genetic diagnosis telomeropathy patients has identified mutations TERT TERC telomerase components but functional consequences...
: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with abasic (AP site) excision repair (BER) intermediate. Cleaving this reversible structure is rate-determining step in initiation of 8-oxoguanine (8-oxoG) for glycosylase 1 (OGG1). The OGG1 AP lyase activity can be increased using small molecule binders, called organocatalytic switches, cleave backbone similar manner as bifunctional glycosylase. In search novel switches we here identify...
Abstract Salivary gland squamous cell carcinomas (SG-SCCs) constitute a rare type of head and neck cancer which is linked to poor prognosis. Due their low frequency, the molecular mechanisms responsible for aggressiveness are poorly understood. In this work we studied role phosphatase DUSP1, negative regulator MAPK activity, in controlling SG-SCC progression. We generated DUSP1 KO clones A253 human cells. These showed reduced ability grow 2D, self-renew ECM matrices form tumors...
8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G : C→T A transversion, removal of utmost importance for cells ensure genomic integrity. For with elevated levels reactive oxygen species this dependency further increased. In past we others have validated OGG1 as a target inhibitors treat cancer inflammation. Here, present optimization campaign that led broadly used tool...
Although widely used in industry, organocatalysis has classically been limited to ex vivo application. In addition, the small molecule activation of enzymes so far exerted by allosteric control. Recently, we reported that molecules can act as organocatalysts for DNA repair enzyme 8-oxoguanine glycosylase 1 (OGG1). The underlying principle allows a full control enzymatic function with potential alleviating oxidative stress genome or new strategy cancer therapy. Organic partake chemical...
Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved the base excision repair (BER) pathway can modify breast and ovarian cancer risk BRCA1 BRCA2 mutation carriers. We previously found that SNP rs34259 uracil-DNA gene (UNG) might decrease In present study, we validated this finding a larger series of familial patients to gain insights into how UNG variant exerts its protective effect. is associated with significant downregulation lower levels damage at telomeres....
Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with abasic excision repair intermediate. For 8-oxoguanine glycosylase 1 (OGG1), cleaving this reversible structure is rate-determining step in initiation of (8-oxoG) DNA. Evolution has led OGG1 use productassisted catalysis approach, where excised 8-oxoG acts as Brønsted for cleavage However, physicochemical properties significantly limit inherent enzymatic turnover. We hypothesized that...
Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with abasic excision repair intermediate. For 8-oxoguanine glycosylase 1 (OGG1), cleaving this reversible structure is rate-determining step in initiation of (8-oxoG) DNA. Evolution has led OGG1 use product assisted catalysis approach, where excised 8-oxoG acts as Brønsted for cleavage However, physicochemical properties significantly limit inherent enzymatic turnover. We hypothesized that...
Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which mainly recognized and excised by the glycosylase OGG1, initiating Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to stress disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line study role of OGG1 at telomeres in response stress. Next, we investigated effects inactivating pharmacologically BER during (OS) conditions...
Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which mainly recognized and excised by the glycosylase OGG1, initiating Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to stress disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line study role of OGG1 at telomeres in response stress. Next, we investigated effects inactivating pharmacologically BER during (OS) conditions...