Lecture 3.pdf

DNA Damage and Mutations Lecture 3 1 At the end of this lecture, students should be able to: • Know types of DNA mutations. • Know causes of DNA damage. • Understand the types of DNA damage. E • Mutation: A change in the nucleotide sequence of a chromosome. They could be seen as somatic...

DNA Damage and Mutations Lecture 3 1 At the end of this lecture, students should be able to: • Know types of DNA mutations. • Know causes of DNA damage. • Understand the types of DNA damage. E • Mutation: A change in the nucleotide sequence of a chromosome. They could be seen as somatic cells mutations , and they are not transmitted. Germ -line mutations seen in gametes, and they are inherited. • Mutations could be seen as: Localized genetic mutations. Chromosomal mutations. I É En if it Genet mitation Main types of point mutations Substitution I nsertion deletion Consequences of mutations: Silent effect missense effect nonsense effect. Trinucleotide repeat expansion n I II I Jem 2 26 G 3 TJ N .U B S . E S jobs'Nsbt 1 atwood'S JIT Langs 2 It amina 3 Stop codon us Ota Huntington disease Fragile X syndrome of 3 Codons a cat Chromosomal mutations Duplications Deletions Inversions Translocation pignut ji 0 G JIA ga Wa k passé IF MG3j 8d7D I.a I1Es.s o o t What causes DNA damage and mutations in cells? Spontaneous normal metabolic processes inside the cell Environmental factors DNA Damage: Most of the DNA damage affects the primary structure of the double helix; • Oxidative processes, • A lkylation of bases, • B ase loss caused by the hydrolysis of bases, • B ulky adduct formation, • DNA crosslinking, and • DNA strand breaks . 0 I 2 3 U 5 6 Oxidative Stress • ROS and can be produced by ultraviolet and ionizing radiations or from other radicals arising from enzymatic reactions . • Increased levels of 8 -oxo -dG in a tissue can serve as a biomarker of oxidative stress . • Repair mechanisms replaces 8 - oxo -dG with thymine this results in a G to T transversion It O To Is Guanine tothyamin É Alkylating agents : • Mainly methylation at different sites of DNA and RNA, can cause neutral, cytotoxic, or mutagenic changes . I T T methyltransferase add methyl group Base Loss An AP site (apurinic/apyrimidinic site ), also known as an abasic site , is a location in DNA (also in RNA but much less likely) that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage. It has been estimated that under physiological conditions 10,000 apurinic sites and 500 apyrimidinic may be generated in a cell daily. Apurination could be spontaneous damage, or occur as intermediates in base excision repair 85 9 t Bulky Adduct Formation Some chemicals are biologically reactive and will form covalent linkages with biological molecules such as DNA and proteins creating large bulky adducts , e.g. benzo[ a ]pyrene . o o lead to cell apoptosis DNA Crosslinking O ccurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them . EEE DNA Strand Breaks Ionizing radiation and chemicals cause DNA crosslinking leading to DNA strand breaks if the damaged DNA undergoes DNA replication. e Could mutations occur during replication? • When the cell replicates its DNA again, the two strands that are produced are no longer the same. • This usually will cause the new cell to die, but sometimes it can cause the cell to divide when it is not supposed to → cancer E 0 How do mutations occur? Replication in 0