A5040858476- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Pharmacogenetics and Drug Metabolism
- Carcinogens and Genotoxicity Assessment
- Epigenetics and DNA Methylation
- BRCA gene mutations in cancer
- Nutrition, Genetics, and Disease
- Estrogen and related hormone effects
- Genetic factors in colorectal cancer
- Protein Tyrosine Phosphatases
- Animal testing and alternatives
- Consumer Attitudes and Food Labeling
- Plant Genetic and Mutation Studies
- Phytoestrogen effects and research
- Yeasts and Rust Fungi Studies
- Cancer therapeutics and mechanisms
- Retinoids in leukemia and cellular processes
- Fungal Plant Pathogen Control
- Telomeres, Telomerase, and Senescence
- Enterobacteriaceae and Cronobacter Research
- Chemical Reactions and Isotopes
Czech Academy of Sciences
2012-2024
Czech Academy of Sciences, Institute of Molecular Genetics
2015-2024
University of Sussex
2021-2023
CRUK/MRC Oxford Institute for Radiation Oncology
2018-2019
Medical Research Council
2018-2019
University of Oxford
2018-2019
Cancer Research UK
2018
Institute of Molecular Genetics
2013-2017
Charles University
2009
Abstract Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the detection and processing of unligated Okazaki fragments other DNA replication intermediates, highlighting such structures as potential sources genome breakage induced by PARP inhibition. Here, we show that PARP1 activity greatly elevated chicken human S phase cells which FEN1 nuclease genetically deleted highest behind forks. inhibitor reduces integrity nascent strands both wild-type during replication, does so − / to an...
Germline mutations in checkpoint kinase 2 ( CHEK2 ), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially published studies. We analyzed germline variants 1,928 high‐risk Czech breast/ovarian (BC/OC) patients and 3,360 population‐matched controls (PMCs). For functional classification of VUS, we developed complementation assay human nontransformed RPE1‐ ‐knockout cells quantifying CHK2‐specific phosphorylation endogenous protein...
In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage (DDR) pathway that coordinates repair and progression through the cell cycle. Extensive modification chromatin flanking lesion ATM kinase RNF8/RNF168 ubiquitin ligases enables recruitment various factors. Among them BRCA1 53BP1 are required for homologous recombination non-homologous end joining, respectively. Whereas mechanisms DDR relatively well understood in interphase cells,...
// Sona Pechackova 1, * , Kamila Burdova Jan Benada 1 Petra Kleiblova 2 Gabriela Jenikova Libor Macurek Department of Cancer Cell Biology, Institute Molecular Genetics the ASCR, CZ-14220 Prague, Czech Republic Biochemistry and Experimental Oncology, Charles University in CZ-12853 These authors have contributed equally to this work Correspondence to: Macurek, e-mail: libor.macurek@img.cas.cz Keywords: WIP1 inhibitor, p53, checkpoint, nutlin-3, breast cancer Received: October 31, 2015...
Cyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. participates feedback loops that activate kinases G2 phase, but why active A2-CDK2 during S phase does not trigger kinase activation remains unclear. Here, we describe change localisation from being only nuclear to cytoplasmic at S/G2 border. We find can PLK1 through phosphorylation Bora, interacts with Bora PLK1. Expression predominately or phospho-mimicking T210D partially rescue arrest...
Abstract DNA single‐strand breaks (SSBs) disrupt replication and induce chromosome breakage. However, whether SSBs breakage when present behind forks or ahead of is unclear. To address this question, we exploited an exquisite sensitivity SSB repair‐defective human cells lacking PARP activity XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these results breakage, sister chromatid exchange, cytotoxicity by a mechanism depends on S phase...
Abstract Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have poor understanding of the specific genetic vulnerabilities that would make cells susceptible such tailored therapy. Moreover, identification interest for targeting BRCA2;p53-deficient tumors acquired resistance polymerase inhibitors (PARPi) through loss PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, identify...
Article19 August 2019Open Access Transparent process E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin loss and Chk1 inhibition Kamila Burdova Department of Oncology, Medical Research Council Institute for Radiation University Oxford, UK Search more papers by this author Hongbin Yang Roberta Faedda Samuel Hume Jagat Chauhan Nuffield Clinical Medicine, Ludwig Cancer Research, Headington, Daniel Ebner Target Discovery Institute, Benedikt M Kessler Iolanda Vendrell...
In response to DNA damage, a cell can be forced permanently exit the cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after damage until terminal exit. This low level not only allows progression, but also promotes at decision point in G2 phase. We find residual Cdk1/2 is required for efficient p21 production, allowing nuclear...
Cells are constantly challenged by DNA damage and protect their genome integrity activation of an evolutionary conserved response pathway (DDR). A central core DDR is composed a spatiotemporally ordered net post-translational modifications, among which protein phosphorylation plays major role. Activation checkpoint kinases ATM/ATR Chk1/2 leads to temporal arrest in cell cycle progression (checkpoint) allows time for repair. Following repair, cells re-enter the recovery. Wip1 phosphatase...
Abstract Most mitotic homologous recombination (HR) events proceed via a synthesis-dependent strand annealing mechanism to avoid crossing over, which may give rise chromosomal rearrangements and loss of heterozygosity. The molecular mechanisms controlling HR sub-pathway choice are poorly understood. Here, we show that human RECQ5, DNA helicase can disrupt RAD51 nucleoprotein filaments, promotes formation non-crossover products during double-strand break-induced counteracts the inhibitory...
The MRN (MRE11–RAD50–NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations the subunit MRE11 cause hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that directly interacts with PIH1D1, a heat-shock protein 90 cochaperone R2TP complex, which required assembly large complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins mammalian target rapamycin 1. MRE11-PIH1D1 interaction...
Orderly progressions of events in the cell division cycle are necessary to ensure replication DNA and division. Checkpoint systems allow accurate execution each cell-cycle phase. The precise regulation levels cyclin proteins is fundamental coordinate with checkpoints, avoiding genome instability. Cyclin F has important functions regulating during G2 checkpoint; however, mechanisms underlying poorly understood. Here, we observe that regulated by proteolysis through β-TrCP. β-TrCP recognizes a...
UV irradiation induces "bulky" DNA photodimers such as (6-4)-photoproducts and cyclobutane pyrimidine dimers that are removed by nucleotide excision repair, a complex process defective in the sunlight-sensitive cancer-prone disease xeroderma pigmentosum. Some bacteria lower eukaryotes can also repair enzymatically simpler mechanisms, but pathways have not been reported normal human cells. Here, we identified mechanism. We show cells employ base involving NTH1, APE1, PARP1, XRCC1, FEN1 to...
In response to DNA damage, the histone PARylation factor 1 (HPF1) regulates PARP1/2 activity, facilitating serine ADP-ribosylation of chromatin-associated factors. While are known for their role in single-strand break repair (SSBR), significance HPF1 this process remains unclear. Here, we investigated impact deficiency on cellular survival and SSBR following exposure various genotoxins. We found that loss did not generally increase sensitivity agents typically induce breaks (SSBs) repaired...
The effects of selected flavonoids on cytochromes P450 in rat liver and small intestineIn recent years, the consumption use dietary supplements containing concentrated phytochemicals (e.g. flavonoids) increased dramatically. Flavonoids, as foreign compounds (xenobiotics), have great potential to modulate activity cytochrome P450s (CYPs), xenobiotic-metabolizing enzymes involved activation detoxification food environmental carcinogens. Thus, aim this study was investigate model glycosylated...
Reactive oxygen species constantly generated as by-products of cellular metabolism readily attack genomic DNA creating mutagenic lesions such 7,8-dihydro-8-oxo-guanine (8-oxo-G) that promote aging. 8-oxo-G:A mispairs arising during replication are eliminated by base excision repair initiated the MutY glycosylase homologue (MUTYH). Here, using formaldehyde crosslinking in mammalian cell extracts, we demonstrate WRN helicase/exonuclease defective premature aging disorder Werner syndrome (WS)...
Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation damage response by suppressing function p53 other targets at chromatin. Here we show that WIP1 promotes through homologous recombination. Loss or inhibition delayed disappearance the ionizing radiation-induced 53BP1 foci S/G2 cells promoted death. We identify breast cancer associated protein 1 (BRCA1) interactor...