Evolution - Causes Flashcards
Mutagenesis
This is the process of mutation formation
What are the endogenous causes of mutagenesis?
DNA replication
Failure in DNA repair
Spontaneous deamniation
Abundant ROS
Abasic sites
Why might mutagenesis occur in DNA replication?
Varying polymerase fidelity
How many bases do polymerase makes per generation?
10^8 with minimal error rates
How might errors occur by polymerases in replication?
In tandem with mismatch repair mechanisms, by insertions/deletaions by replication slippage
What are the repair pathways?
Mismatch Repair
Base-excision repair
Nucleotide-excision repair
Translesion
Non-homologous end joining
What disease does failure in DNA repair often result in?
cancer.
What does NER pathway mutation cause?
Xeroderma pigmentosum which makes people prone to skin cancer.
Why might translesion repair system result in mutation?
It increases polymerase active site to bypass DNA lesions with expense of increased error rate due to lower fidelity
Fidelity
A polymerase ability to accurately replicate a template.
Why does translesion repair reduce polymerase fidelity?
Because high fidelity polymases struggle to pass damaged bases, stalling DNA replication.
What happens in spontaneous deamination?
An amine is lost resulting in NT change.
What are examples in deamination nucleotide change?
C to U, adenine to hypoxanthine, guanine to xanthine, 5-methyl cytosine to thymine
What does cytosine damination result in?
A;T mutaiton
How many SNT hereditary diseases result from deamination?
33%
How are ROS naturally produced?
By ETC, important in many cell processes, with high quantities damaging DNA.
What is an example of ROS damage?
8’ carbon guanine forming 8-oxoguanine with incorrect pairing with adenine instead of cytosine
What diseases are abundant ROS often involved in?
Alzheimers, cancer and heart failure
Why does ROS result in alheimers?
Mitochondrial autophagy results in ROS increasing due to nutrient deprivation and oxygen
How are abasic sites formed?
Spontaneous hydrolysis or DNA glycolyase cleavge, often repaired by TLS
What are the EXOGENOUS mutagenic causes?
Ionizing Radiation
Ultraviolet Radiation
Alkylating agents
Polycyclic aromatic hydrocarbons
Aflatoxin
How does ionizing radiation cause mutagenesis?
Induce DNA breaks as well as radiolysis of H2O producing ROS.
How does UV induce mutagenesis?
Pyrimidine dimerisation and pyrimidine photoproducts with DNA helical distortion
What can UV damage be repaired by?
NER and TLS
What do alkylating agents cause?
Abasic site formation due to their affinity for nitrogen.
What are examples of alkylating agnets?
Methyl methanosulfonate
Nitrogen mustard gas
Ethyl methanosulfonate
Alkylating agents
These have capabilites to prevent DNA replication, reacting with nucleophiles forming covalent bond
How does mustard gas prevent DNA replication?
Induces cross-linkage
Ethyl methanosulfonate
This results in guanine alkylation producing point mutations
CytochromeP450 system
A hemeprotein metabolising a variety of drugs and xenobiotics.
How might aromatic amines cause alkylating agent formation?
When metabolised by cytochromeP450 system
What does aromatic amine metabolism cause?
C8 guanine lesions and frameshift/base mutations
Polycyclic Aromatic Hydrocarbons
Contain two or more aromatic rings, found in tobacco smoke, automobile exhausts, and fossils fuels
DNA adducts
DNA segments bound to cancer causing chemicals
Alfatoxing
Metabolised by CYP450 forming adducts with guanine N7
What is alfatoxin the main cause of?
Hepatocellular carcinoma
