DNA mutations Flashcards
Ways to cause DNA mutation
Spontaneous
Endogenous factors
Exogenous factors
what are common spontaneous DNA damage? (2)
Hydrolytic depurination:
This is a process where a purine base (adenine or guanine) is removed from the DNA molecule. It happens when water breaks the bond between the base and the sugar in the DNA backbone, leaving a gap where the base used to be. This can lead to mutations if not repaired.
Hydrolytic deamination of base:
his is a process where an amino group is removed from a base in the DNA. For example, cytosine can be deaminated to become uracil. This change can also lead to mutations if not corrected.
what DNA bases are prone to be deaminated?
What do these changes cause?
Hypoxanthine resembles
guanine and base pairs with
cytosine- Hypoxanthine is formed through the deamination of adenine.
Xanthine, like guanine, pairs
with cytosine- Xanthine is formed through the oxidation of hypoxanthine.
Uracil is similar to thymine, which pairs with adenine in DNA- Uracil is formed through the deamination of cytosine, where an amino group is removed from cytosine.
thymine = no deamination
These changes in bases can cause errors in DNA replication and transcription if not repaired, potentially leading to genetic mutations.
what are the chemical reactions that cause DNA mutations?
Hydrolysis- breaking of bond by adding water= leads to the loss of bases (depurination and depyrimidination)= AP sites= muatation
Oxidation- Gain of Oxygen and loss of Hydrogen=base mispairing =mutations
Methylation- addition of Methyl Group to DNA bases= altering base pairing= mutation
How are endogenous factors produced?
Endogenous factors are produced by the metabolism of the cell.
what are the endogenous factors that can cause DNA mutations
Superoxide (.O2-)
Hydrogen peroxide (H2O2)
Hydroxyl radicals (.OH)
what are the exogenous factors that can cause DNA damage?
High energy radiation
- UV
- X-rays
- γ-rays
Organic compounds
Inorganic compounds
what type of UV cause DNA damage
UV-C contains most energy of UV radiation – causes most DNA damage
UV-B contains less energy than UV-C but is well absorbed by DNA
UV-A relatively harmless in terms of DNA damage.
what kind of DNA damage does UV radiation cause?
UV radiation can cause two pyrimidine bases (thymine-thymine, thymine-cytosine, or cytosine-cytosine) to become covalently linked= forms a cyclobutane ring= This creates a kink in the DNA backbone disrupting normal base pairing and blocking transcription and replication.
what do reactive oxygen species cause?
DNA base damage at multiple sites.
what kind of damage to X rays and y-rays cause.
which one is more severe?
what does the more severe one cause if it not properly repaired (3).
they produce single and double strand breaks in the backbone of DNA.
Single-strand breaks are generally less severe than double-strand breaks.
Double-strand breaks can lead to chromosomal rearrangements, mutations, or cell death if not properly repaired.
What organic compounds can cause DNA damage.
Alkylating agents transfer alkyl groups (methyl-, ethyl-groups etc.) on electron rich atoms in DNA e.g. Oxygen and Nitrogen.
What are the Consequences oF DNA modifications.
- what does modification of bases cause?
- what does change base pairing cause?
- what does double strand breaks lead to ?
- how do mutations in germ cells occur?
- what does crosslinking of DNA strands INHIBIT?
- Modifications of bases can change base pairing= change in reading frame
- Changed base pairing can result in a mutation
- Double strand breaks can lead to gene rearrangement and loss of numerous genes
- Mutations in germ cells are inherited
- Crosslinking of DNA strands inhibits transcription, translation and can kill a cell.
what are the types of mutations?
Point mutation – change of a bp:
- Silent Mutation: No change in the amino acid sequence.
- Missense Mutation: A different amino acid is incorporated.
- Nonsense Mutation: A stop codon is introduced, truncating the protein.
Deletion – one or more bp are lost
Insertion - one or more bp are inserted
what do deletions and insertions cause?
Both deletions and insertions can cause frameshift mutations, which alter the reading frame of the gene. This results in a completely different amino acid sequence, often leading to non functional or truncated proteins due to the introduction of premature stop codons.
where else can mutations occur other than proteins?
Mutations in promoter/activator regions can modify gene expression and regulation
Mutations in exon/intron boundaries can disrupt the reading frame of a protein
what are the Main mechanisms to correct DNA damage? (3)
Excision and elimination of the damaged nucleotide(s) or bigger lesions (damage to DNA structure).
A DNA polymerase fills the gap using the other strand as a template
DNA ligase heals the nick in the DNA strand
BASE Excision repair How does it work?
- DNA glycosylases scan the DNA for alterations
- Altered bases are recognised and then is hydrolysed
- Endonuclease and phosphodiesterase remove sugar phosphate backbone and replaced with a new nucleotide.
- DNA polymerase fills gap and ligase heals the nick
NUCLEOTIDE excision repair. how doe it work?
Excision nuclease recognises the damage
One cut is made on each side of the lesion
DNA helicase removes the entire portion of the damaged strand
DNA polymerase fills gap and ligase heals the nick
DNA Repair- Chemical Reversal.
what happens? + exmaples (3)
what does it NOT involve?
- Restricted subset of proteins designed to repair specific damage (e.g. pyrimidine dimers, O4- or O6-alkylguanine)
- does not involve breakage of the phosphodiester backbone
what does photolyase reverse?
what does methyl guanine methyl transferase (MGMT) reverse?
what can cells be used to reverse?
photolyase reverses pyrimidine dimers
(MGMT) reverses methylation of guanine bases.
certain methylation of cytosine and adenine can also be reversed by cells
which type of mutation does not affect the length of proteins?
Missense Mutation: A different amino acid is incorporated.
can Nucleotide excision repair be activated by modification on a SINGLE base?
what about Base Excison repair?
No!
Nucleotide excision repair (NER) is activated when there are bulky DNA lesions
Base excision repair (BER) can indeed be activated by a single base alteration.
