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Mechanistic insights into alcohol-induced interstrand crosslink repair by the nuclease SLX4-XPF-ERCC1
Havlíková, Jana ; Šilhán, Jan (advisor) ; Lux, Vanda (referee)
Alcohol ranks among the most widely used recreational drugs in the world, even though it is considered a risk factor for more than 200 diseases. The primary negative impact of alcohol lies in its metabolite, acetaldehyde, which, as a highly reactive compound, can form mutagenic adducts and interstrand crosslinks (ICLs) in DNA. The formation of ICLs, which have a covalent nature and block the separation of the two DNA strands during replication, is one of the important causes of mutagenesis and carcinogenesis. To maintain genomic stability, repair mechanisms have evolved. One of them is a pathway that uses proteins encoded by Fanconi anaemia genes, whose defects lead to the disease of the same name. Defects in repair pathways can be particularly dangerous in individuals with impaired functionality in other metabolic pathways, such as alcoholics and individuals with mutations in genes that result in the accumulation of toxic acetaldehyde. The theoretical part of this thesis deals with alcohol metabolism, in vivo acetaldehyde formation, and its interactions with DNA. The ICL and their repair pathways are characterized in more detail. A separate chapter is dedicated to Fanconi anaemia. The practical part of this work focuses on the preparation of site-specific acetaldehyde- induced ICL (AA-ICLs) and the study...
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Molecular mechanisms of carcinogenic effects of alcohol
Vepřková, Jana ; Kábelová, Adéla (advisor) ; Novotná, Božena (referee)
Alcohol (ethanol) enters the human body mainly through ingestion of alcoholic beverages and its chronic consumption is considered a worldwide socio-economic problem. Besides others, alcohol consumption increases the risk of development of breast, liver, colorectal and upper aerodigestive tract cancer. In the liver, ethanol is metabolised into toxic acetaldehyde which is the main cause of DNA damage leading to cancer development. Acetaldehyde covalently interacts with nucleotides in the DNA forming DNA adducts such as N2 -ethylidene-2'-deoxyguanosine or S- and R-α-methyl-γ-hydroxy-1,N2 - propano-2′-deoxyguanosine. Acetaldehyde can also interact with proteins and disrupt their function. Ethanol metabolism by cytochrome P450 2E1 leads to production of reactive oxygen species, that subsequently damage cellular molecules such as lipides and DNA. Ethanol also initiates carcinogenesis through aberant DNA methylation or interference with retinoic acid metabolism. In cancer development, alcohol interacts with other environmental and genetic factors, which can increase the risk of developing cancer in predisposed individuals.
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