Mutations and DNA Damage Flashcards
Transitions Point Mutation
change a purine (A/G) to a different purine (G/A) OR a pyrimidine (T/C) to a different pyrimidine (C/T)
Transversions Point Mutation
change a purine to a pyrimidine or vice versa
Missense Point Mutation (protein coding gene)
mutation changes a codon so that it causes a different amino acid to be incorporated into the encoded polypeptide chain
Nonsense Point Mutation (protein coding gene)
changes an amino acid-encoding codon to a stop codon
Silent Point Mutation (protein coding gene)
change the base in the DNA and RNA, but do not affect the amino acid
Neutral Point Mutation
occur in noncoding regions of DNA & do not affect gene products or gene expression
Point Mutation
Substitution
Frameshift Mutation
Deletion or Insertion of a number of bases
Frameshift mutaitons alter
Multiple codons
Point mutations alter
One codon
Loss of Function Mutation
reduce the mutated gene’s function - usually recessive to the wild-type allele
Null Mutation
occurs when the mutation causes total loss of the gene product
Haploinsufficiency
when one wild-type allele is not enough to produce the wild-type phenotype
because ½ of the protein is not sufficient to do the job
Dominant-Negative Mutations
cause the mutant allele to produce a mutated protein
- even if the wild-type allele still makes normal protein, the mutated protein negates (cancels out) the function of the wild-type protein
- therefore, the mutation produces the mutant phenotype even if the wild-type gene copy is still intact
Gain of Function Mutation
Increases gene function (usually dominant)
Gain of Function mutations may create a structural change
-the Ras gene encodes a key signaling protein that regulates whether cells grow, migrate, and die
-cancer cells frequently mutate Ras in such a way that the protein cannot be turned off
Somatic Mutations
are those that occur in any body cell other than germ cells
-are not transmitted to offspring
-have greater impact if they are …
*dominant
*occur on the X chromosome in males
*occur earlier in development
Germ Line Mutations
take place in germ cells
-only type of mutation capable of being transmitted to offspring
Spontaneous Mutations (slippage, oxidative damage, tautomeric shifts)
-changes in the nucleotide sequence of genes that occur naturally
-no specific agents are associated with their occurrence (unlike induced mutation)
-arise because of normal cellular processes & reactions
*ex – DNA polymerase errors in DNA replication
DNA Polymerase Has Intrinsic Proofreading Ability
-DNA polymerases have intrinsic 3’ to 5’ exonuclease activity
-allows them to correct most replication errors
-DNA polymerase make a mistake once every 100,000 bases
*corrects about 99% of these errors
*equates to an error rate of ~ 10-7
mostly mispairing/point mutations
Replication Slippage
-most common when polymerase replicates regions of DNA containing tandemly repeated sequences
-may cause insertions/deletions that lead to frameshift mutations
Replication Slippage happens when
-when polymerase slips or stutters as it moves along the DNA
-the lagging strand template loops out and becomes displaced during replication
Oxidative Damage
from reactive oxygen species (ROS) generated by normal cellular reactions
Reactive Oxygen Species (ROS)
-examples of ROS include:
*superoxide anions (O2-)
*hydroxyl radicals (OH-)
*hydrogen peroxide (H2O2)
-ROS may lead to modification or loss of bases in the DNA, or to single-strand breaks
Tautomeric Shifts
change covalent structure of a N base and permit H bonding between non-complementary bases
-results in permanent base pair change & mutation
How does a tautomeric shift result in a permanent base change?
- a base in the parental DNA strand undergoes a tautomeric shift
- during DNA replication, that tautomer participates in non-standard base-pairing (A:C, not A:T)
- when replicated later on, the strand containing “C” at that position recruits a “G”, not the original “A”
the base at this position is now permanently changed in this cell & all its descendants
Ionizing Radiation
-ionizes stable molecules and atoms, transforming them into highly reactive free radicals with unpaired electrons
*alter bases in DNA
*break phosphodiester bonds in the DNA backbone
*lead to double-strand breaks
*cause chromosomal deletions, translocations, and fragmentation
-20% of human radiation exposure comes from human-made sources
-majority of our exposure comes from radon gas, cosmic rays, and natural soil radioactivity
Alkylating Agents
-donate an alkyl group (e.g. CH3 or CH2CH3) to an amino or keto group in a nucleotide
*alter bp affinities & lead to transitions
-mustard gas from WWI was an alkylating agent that creates a base analog that pairs with thymine
Intercalating Agents
-wedge between base pairs of DNA
-cause distortion of DNA structure & induce unwinding
*leads to insertions/deletions during replication
Adduct Forming Agents
-covalently bind DNA & interfere with replication and repair (causing slippage)
-examples include acetaldehyde (cigarette smoke) & heterocyclic amines (meats)
