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The role of 53BP1 in the cellular response to double-strand DNA breaks
Liďák, Tomáš ; Macůrek, Libor (advisor) ; Rösel, Daniel (referee)
DNA damage may result in various pathological conditions and contributes to aging and development of cancer. Evolutionarily conserved DNA damage response prevents the acumulation of mutations and protects against genomic instability. Tumor suppressor p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DNA double-strand breaks (DSB) and is a canonical component of ionizing radiation-induced foci which are formed at DNA DSB following radiation exposure. Recently, new insights have been gained into its functions in the DNA damage response. Apart from its subtle role in the DNA damage checkpoints signaling, 53BP1 is a well established player in the DNA DSB repair pathway choice. The outcome of DNA repair is influenced by 53BP1 in several contexts. 53BP1 controls 5' end resection at DNA ends, improves DSB repair in heterochromatin, promotes the mobility of uncapped telomeres and mediates synapsis of DNA ends during V(D)J and class switch recombination. 53BP1 contributes to repair defect in BRCA1 (breast cancer type 1 susceptibility protein)-deficient cells, which may have an impact on the treatment of some types of breast cancer. The aim of this bachelor's thesis is to summarize new findings about the role of 53BP1 in the cellular response to DNA DSB. Powered by TCPDF (www.tcpdf.org)
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The influence of xenobiotic metabolizing enzymes and transporters on the incidence of colorectal cancer and chemotherapy outcome
Krus, Ivona ; Souček, Pavel (advisor) ; Králíčková, Milena (referee) ; Hodis, Jiří (referee)
Introduction: Colorectal cancer (CRC) is one of the most frequent malignancies and affects approximately 5% of worldwide population. More than 75% of CRC cases represent sporadic forms. Susceptibility to nonhereditary CRC is significantly influenced by polymorphisms and mutations in low-penetrance genes. Variations in biotransformation and DNA repair genes may result in acumulation of toxins and DNA damage in cells leading to the development of cancer. Furthermore, different gene expression profiles of membrane transporters affecting the accumulation of anticancer drugs in tumour cells, e.g. ABC drug transporters, may largely influence inter-individual variability in drug response and chemotherapy outcome. The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal cancer. This study followed selected genetic alterations in xenobiotic-metabolizing enzymes (CYP1B1, GSTM1, GSTT1, GSTP1, NQO1 and EPHX1) and genes involved in response to DNA damage (CHEK2 and NBN), as potential CRC susceptibility factors. Another aim of this study was to investigate expression profile of all human ABC transporter genes to follow their prognostic and predictive potential in colorectal carcinoma. Materials and methods: The polymorphisms and other...
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The application of functional tests to measure DNA repair capacity in molecular epidemiological studies
Slyšková, Jana ; Vodička, Pavel (advisor) ; Hampl, Aleš (referee) ; Kment, Milan (referee)
DNA repair is a vital process of a living organism. Inherited or acquired defects in DNA repair systems and cellular surveillance mechanisms are expected to be important, if not crucial factors in the development of human cancers. DNA repair is a multigene and multifactorial process which is most comprehensively characterized by the phenotypic evaluation of DNA repair capacity (DRC). DRC represents a complex marker with high informative value, as it comprises all genetic, epigenetic and non-genetic factors, by which it is modulated. Accordingly, DRC reflects the actual capability of the cell, tissue or organism to protect its DNA integrity. The present PhD study was focused on investigating DRC, which specifically involves base and nucleotide excision repair pathways, in human populations with different characteristics. The main aim was to answer substantial questions on the possible use of DRC as biomarkers in epidemiological studies. The study was in fact designed to understand the extent of physiological variability of DRC in a population, its modulation by genetic and non-genetic factors, tentative adaptability to high genotoxic stress and, finally, its involvement in cancer aetiology. In order to explore these issues, DRC, in respect to genetic and environmental variability, was investigated...
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Intracellular signalling of Chk2 kinase and impact of its defects in oncogenesis
Stolařová, Lenka ; Kleibl, Zdeněk (advisor) ; Brábek, Jan (referee)
Chk2 (checkpoint kinase 2), a regulatory protein of the cell cycle checkpoints, is coded by CHEK2 gene. Chk2 belongs to serine/threonine kinase family and its dominant activity is in regulation and signal distribution of intracellular response to DNA damage. The upstream regulator of Chk2 protein is the ATM kinase that activates Chk2 by its phosphorylation on Thr68 localized in FHA domain. This in turn leads to the conformation change inducing homodimerization of Chk2 protomers and their activating phosphorylation within their kinase domains. Upon phosphorylation, catalytically active Chk2 protomers dissociate and phosphorylate various intracellular proteins (incl. p53, E2F-1, BRCA1, Cdc25A a C, BRCA2 a PLK3). By regulation of these proteins, Chk2 contributes to the cell cycle arrest, regulation of DNA repair and apoptosis. Germline mutations in CHEK2 gene were identified with the increased frequency in many human cancers, including breast and colorectal cancer. Hence, the failure of Chk2 intracellular activity contributes to the process of malignant transformation.
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Gene PALB2 and its role in breast cancer
Zdařilová, Klára ; Janatová, Markéta (advisor) ; Žáčková Suchanová, Jiřina (referee)
Breast cancer is the most common cancer among women in the Czech Republic. Mutations in two major predisposition genes, BRCA1 and BRCA2, account only for 16 % of familial risk of breast cancer. Gene PALB2 was discovered in 2006 as a tumor suppressor. Protein product of PALB2 plays a major role in pathway of DNA repair of double-strand breaks through the homologous recombination mechanism. PALB2 links BRCA1, BRCA2 and RAD51 and is required for their recruitment to DNA damage foci and initiate homologous recombination. In a response of DNA damage PALB2 participates on regulation of the cell cycle. Protein function of PALB2 is necessary to maintain the integrity of the genome and in case of loss this function, because of the gene inactivation, it leads to genomic instability, which may be the basis for the development of tumorogenesis. Heterozygous mutations in PALB2 increase the risk of breast cancer predisposition, these mutations has been demonstrated even in pancreatic cancer and less often in ovarian cancer. Therefore, it is important to analyze truncating mutations in the PALB2 gene in BRCA1/2-negative patients from families with a strong history of hereditary breast cancer. The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech hereditary...
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Vztah mezi genetickými polymorfismy DNA reparačních genů a jejich expresí u zdravé populace (s výhledem na stanovení u onkologických pacientů).
Hánová, Monika ; Vodička, Pavel (advisor) ; Bencko, Vladimír (referee) ; Černá, Marie (referee)
DNA damage response is a complex system responsible for protection of a cell against internal and external DNA damaging agents and in maintaining genome integrity. Many of genes participating in DNA damage response pathways are polymorphic. Genetic polymorphisms in coding and regulatory regions may have impact on the function of proteins encoded by the genes. Phenotypic effect of single nucleotide polymorphisms (SNPs) is subject of investigation in connection with the ability of a cell to manage genotoxic stress and subsequently, in relation to cancer susceptibility. The aim of this thesis was to evaluate the association between SNPs in DNA repair genes (hOGG1, XRCC1, XPC) and cell cycle genes (TP53, p21CDKN1A , BCL2 and BAX) and their mRNA expression in peripheral blood lymphocytes from individuals occupationally exposed to styrene and control individuals. The aim was extended to analyses of relationships between mRNA expression levels of the above-mentioned genes and markers of exposure to styrene (concentration of styrene in blood and in air), markers of DNA damage (single strand breaks - SSBs, and endonuclease III specific sites - Endo III sites) and the base excision repair (BER) capacity, by means of γ-irradiation specific DNA repair rates and oxidative repair. Study on the group of healthy...
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Implication of eukaryotic DNA repair machinery in viral replication
Hron, Tomáš ; Španielová, Hana (advisor) ; Harant, Karel (referee)
Eukaryotic DNA damage response is an important mechanism which ensures genome stability. Its components are also mobilized during viral infection as a reaction against extraneous nucleic acid. Additionally, DNA repair machinery seems to be activated by some viruses purposely to provide their replication. This activation is mediated mainly by viral proteins which are able to interact with cellular factors. In many cases, key components of DNA damage mechanisms are associated with viral replication centre and likely participate in this process. Furthermore, cellular DNA damage signaling is exploited to provide competent environment for viral reproduction. However, particular mechanisms how these cellular factors participate in viral infection are still largely unclear. In this thesis, the principles of relationship between viral infection and eukaryotic DNA damage response are summarized and main viral families which are known to activate and utilize these mechanisms for its genom replication are described.
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Structure, function and importace of BRCA 1protein
Hojný, Jan ; Falk, Martin (referee) ; Kleibl, Zdeněk (advisor)
Studies of factors contributed to the development of hereditary breast and ovary cancers lead to the discovery of Breast Cancer 1 gene (BRCA1). The protein product of this tumor suppressor gene is nuclear phosphoprotein that plays a critical role in DNA repair and it is required for genome integrity control. The BRCA1 protein is the key component for correct assembly of reparation complexes formed in sites of DNA double strand breaks. Furthermore, BRCA1 protein is implicated in regulation of cell cycle checkpoints and it is also involved in regulation of gene expression in response to DNA damage. These activities suggest that BRCA1 protein plays a crucial role in orchestration of intracellular response to genotoxic DNA damage. Loss of BRCA1 functions leads to the DNA-damage repair mechanisms failure resulting in genomic instability and a tolerance of genomic alterations in affected cells. The genomic instability is the initial step toward early malignant transformation of cells lacking BRCA1 proteins. The aim of this work is to summarize the information about structure, functions known and the importance of BRCA1 protein with respect to the current discoveries enabling elucidation of versatile BRCA1-containing multiprotein complexes in which BRCA1 protein acts as the multiplatform interacting...
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