A5068292360- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- Genomics and Chromatin Dynamics
- Fungal and yeast genetics research
- Advanced Breast Cancer Therapies
- Cancer therapeutics and mechanisms
- Ubiquitin and proteasome pathways
- Chronic Myeloid Leukemia Treatments
- Cytomegalovirus and herpesvirus research
- CRISPR and Genetic Engineering
- Monoclonal and Polyclonal Antibodies Research
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Protist diversity and phylogeny
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Carcinogens and Genotoxicity Assessment
- Epigenetics and DNA Methylation
- Synthesis and Biological Evaluation
- PARP inhibition in cancer therapy
- Acute Myeloid Leukemia Research
- Autophagy in Disease and Therapy
- Cancer, Hypoxia, and Metabolism
Ollscoil na Gaillimhe – University of Galway
2011-2024
Case Western Reserve University
2011
University of Maryland, Baltimore
2011
Albert Einstein College of Medicine
2011
Montefiore Medical Center
2011
The University of Texas at San Antonio
2011
Neurosciences Institute
2011
University of Genoa
2011
Queen's University Belfast
2011
Belfast City Hospital
2011
Minichromosome maintenance 2-7 proteins play a pivotal role in replication of the genome eukaryotic organisms. Upon entry into S-phase several subunits MCM hexameric complex are phosphorylated. It is thought that phosphorylation activates intrinsic DNA helicase activity, thus allowing formation active forks. Cdc7, Cdk2, and ataxia telangiectasia Rad3-related kinases regulate progression known to phosphorylate Mcm2 subunit. In this work, by vitro kinase reactions mass spectrometry analysis...
Corrado Santocanale, Karuna Sharma, and John F.X. Diffley Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, EN6 3LD, UK; Department of Genetics, Roswell Park Institute, Buffalo, New York 14263 USA
Abstract Cdc7 is an evolutionarily conserved kinase that regulates S phase by promoting replication origin activation. Down-regulation of small interfering RNA in a variety tumor cell lines causes abortive phase, leading to death either p53-independent apoptosis or aberrant mitosis. Unlike fork blockade, Cdc7-depleted cells do not elicit robust checkpoint response; thus, inhibitory signals preventing additional cycle progression are generated. In normal fibroblasts, however, p53-dependent...
AbstractThe Dbf4p/Cdc7p protein kinase is essential for the activation of replication origins during S phase. The catalytic subunit, Cdc7p, present at constant levels throughout cell cycle. In contrast, we show here that regulatory Dbf4p, oscillate Dbf4p absent from cells G1and accumulates and G2 phases. rapidly degraded time chromosome segregation remains highly unstable pre-Start G1 rapid degradation requires a functional anaphase-promoting complex (APC). Mutation sequence in N terminus...
Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates inhibition can cause selective tumor-cell death a p53-independent manner, supporting the rationale for developing small-molecule inhibitors treatment of cancers. In this paper, synthesis and structure-activity relationships 2-heteroaryl-pyrrolopyridinones, first potent inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one,...
Aberrant neuronal re-entry into the cell cycle is emerging as a potential pathological mechanism in Alzheimer disease (AD). However, while cyclins, cyclin dependent kinases (CDKs), and other mitotic factors are ectopically expressed neurons, many of these proteins also involved physiological processes, generating continued debate on whether such markers truly indicative bona fide process. To address this issue, here we analyzed one minichromosome maintenance (Mcm) that plays role DNA...
Chromatin replication involves duplicating DNA while maintaining epigenetic information. These processes are critical for genome stability and preserving cell-type identity. Here we describe a simple experimental approach that allows chromatin to be captured its content analysed after in vivo labeling of by cellular polymerases. We show this technique is highly specific proteins bound the replicated can analyzed both immunological techniques large scale mass spectrometry. As proof concept...
Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in fork stabilization checkpoint responses, must be tightly regulated during cell cycle to prevent accumulation damage. In this study, we used quantitative proteomics approach identified USP9X as novel CLASPIN-interacting protein. deubiquitinase involved signaling survival pathways whose tumor suppressor or oncogenic activity...
DNA replication initiates from multiple origins, and selective CDC7 kinase inhibitors (CDC7is) restrain cell proliferation by limiting origin firing. We have performed a CRISPR-Cas9 genome-wide screen to identify genes that, when lost, promote the of cells treated with sub-efficacious doses CDC7i. found that loss function ETAA1, an ATR activator, RIF1 reduce sensitivity CDC7is allowing synthesis occur more efficiently, notably during late S phase. show partial inhibition induces mainly...
Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating activity response to stress have been reported, supporting the opposing notions that either plays an active role under these conditions or, conversely, is a final target inactivated by checkpoint response. We developed new immnunological reagents study properties of human cells challenged with ribonucleotide reductase inhibitor hydroxyurea or topoisomerase II etoposide. show Cdc7·Dbf4...
DNA primase activity of the yeast polymerase-primase complex is related to two polypeptides, p58 and p48. The reciprocal role these protein species has not yet been clarified, although both participate in formation active center enzyme. gene encoding subunit cloned by screening a lambda gt11 genomic library, using specific anti-p58 antiserum. Antibodies that inhibited could be purified lysates Escherichia coli cells infected with recombinant bacteriophage containing entire gene, which we...
Cdc7 kinase is a key regulator of the S-phase cell cycle, known to promote activation DNA replication origins in eukaryotic organisms. inhibition can cause tumor-cell death p53-independent manner, supporting rationale for developing inhibitors treatment cancer. In this paper, we conclude structure-activity relationships study 2-heteroaryl-pyrrolopyridinone class compounds that display potent inhibitory activity against kinase. Furthermore, also describe discovery 89S,...
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. inhibition through siRNA or prototype small molecules causes p53 independent apoptosis tumor cells while reversibly arresting cell cycle progression primary fibroblasts. This implies that could be considered potential target for anticancer therapy. We previously reported pyrrolopyridinones (e.g., 1) are potent and selective inhibitors kinase, with good cellular potency vitro ADME properties but...
Article4 June 2020Open Access Source DataTransparent process CDC7 kinase promotes MRE11 fork processing, modulating speed and chromosomal breakage Michael D Rainey orcid.org/0000-0001-9777-873X Centre for Chromosome Biology, School of Natural Sciences, National University Ireland Galway, Search more papers by this author Aisling Quinlan orcid.org/0000-0003-2888-0057 Chiara Cazzaniga orcid.org/0000-0002-7693-9167 Sofija Mijic Institute Molecular Cancer Research, Zurich, Switzerland Oliviano...
The monoclonal antibody (mAb) 21A6, which specifically inhibits yeast DNA primase activity, has been used to verify whether only one of the two polypeptides heterodimeric (48 and 58 kDa) was responsible for function in vitro. Immunoaffinity chromatography a crude extract from cells Saccharomyces cerevisiae on mAb 21A6 protein A-Sepharose 6B column allowed purification p48 polypeptide an isolated form. This not derived through dissociation four-subunit polymerase alpha-primase complex, can be...
Formation of pre-replicative complexes at origins is an early cell cycle event essential for DNA duplication. A large body evidence supports the notion that Cdc6 protein, through its interaction with origin recognition complex, required complex assembly by loading minichromosome maintenance proteins onto DNA. In fission yeast and Xenopus, this reaction known as licensing chromatin replication also requires newly identified Cdt1 protein. We studied role hCdt1 protein in duplication human...
Cdc7 kinase has recently emerged as an attractive target for cancer therapy and low-molecular-weight inhibitors of have been found to be effective in the inhibition tumor growth animal models. In this paper, we describe synthesis structure−activity relationships new 1H-pyrrolo[2,3-b]pyridine derivatives identified kinase. Progress from (Z)-2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one (1)...