VIII.
MUTATION AND
DNA REPAIR
Yudy Tjahjono, [Link]., [Link].
MUTATION
an inherited change in the genetic
material of an organism.
BY
LOCATION:
BY CAUSE OF
MUTATION:
KEYWORDS
Mutagens vs. teratogens
Germline vs. somatic mutation
Spontaneous vs. induced mutations
A low spontaneous mutation rate is achieved by 3
successive accuracy-enhancing steps
MUTATION AND REPAIR
DNA Replication Errors
- DNA replication errors can be either point
mutations, or small insertions or deletions.
-Base-pair substitution mutations can result
from “wobble” pairing:
A normal form of the base-pairs with an
incorrect partner due to different spatial
positioning of the atoms involved in H-bonding.
Normal and wobble base pairing in DNA
G-T A-C
G-A T-C
TYPES OF MUTATION
POINT MUTATION
Single nucleotide base is changed, inserted or deleted from
a DNA or RNA sequence of an organism's genome
POINT MUTATION IN RNA
TYPES OF MUTATION
Silent mutations – produce no change in amino
acid sequence (due to degeneracy of the
genetic code.) (aka synonymous mutations).
•CUU codes for leucine, but so does CUC,
CUA, CUG, UUA, and UUG.
Neutral mutations result when amino acid
substitutions do not change protein function.
Similar amino acids can be substituted for
each other – isoleucine for leucine.
TYPES OF MUTATION
Nonsense mutations – change in codon to UGA,
UAA, or UAG.
• Resulted in premature stopping of protein
synthesis.
• They can be lethal or severe in phenotype.
Missense mutations result when the amino acid
substitution changes protein function.
Caused occasionally by Temperature sensitivity
TYPES OF MUTATION
•Transition mutations – Pu to Pu, Py to Py.
•G🡪A & A 🡪 G
•T 🡪 C & C 🡪 T
•Transversion mutations – Pu to Py or Py to
Pu.
•A 🡪 T, A 🡪 C, G 🡪 T, or G 🡪 C.
•T 🡪 A, T 🡪 G, C 🡪 A, or C 🡪 G.
TYPES OF MUTATION
insertion/deletions of base pairs.
•The 2nd most common type of mutations.
•This can cause frameshifts.
•deletions or insertions of one or two bases
usually results in dramatic differences in
protein production.
TYPES OF MUTATION
TYPES OF MUTATION
Nonsense Mutation and Its Effect
CAUSES OF MUTATION:
Spontaneous Mutations
- All types of point mutations can occur spontaneously, during S,
G1 and G2 phases of the cell cycle, or by the movement of
transposons.
- The spontaneous mutation rate in eukaryotes is between
10-4-to-10-6 per gene per generation, and in bacteria and
phages 10-5-to-10-7/
gene/generation.
- Transposons (mobile DNA sequences): a DNA sequence that
can change its position within a genome, sometimes creating
or reversing mutations and altering the cell's genetic identity
and genome size
SPONTANEOUS MUTATION
A. Tautomerism --- A base is changed by the repositioning of a
hydrogen atom, altering the hydrogen bonding pattern of that
base resulting in incorrect base pairing during replication.
B. Depurination --- Loss of a purine base (A or G) to form an
apurinic site (AP site)
C. Deamination --- Hydrolysis changes a normal base to an atypical
base containing a keto group in place of the original amine
group.
D. Slipped strand mispairing (SSM) --- Denaturation of the new
strand from the template during replication, followed by
renaturation in a different spot ("slipping"). This can lead to
insertions or deletions.
KETO ENOL
Tautomerism
Depurination
Deamination
or
Hydrolisis
Base Modifying (Deamination) agents
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Base Modifying (Deamination) agents
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Slipped Strand Mispairing (SSM)
-Common in short (3-4 bases) tandem (direct)
repeate sequences (STR)
-Can results in Shift of mRNA Reading Frame
NORMAL SLIP FORWARD SLIP BACKWARD
DELETION INSERTION
Jennifer K. Sehn, Clinical Genomics, 2015
CAUSES OF MUTATION
INDUCED MUTATION
CAUSED BY MUTAGENS
A. CHEMICALS
B. RADIATION
C.
Mutagenic effects of the base analog
5-bromouracil (5BU)
Alkylating Agents
Structure of some alkylating mutagens
Ionizing Radiation
Production of thymine dimers by ultraviolet
light irradiation
Cyclobutane ring
“sometimes” cause cells to lose control over their
division
Ionizing Radiation
Production of thymine dimers by ultraviolet
light irradiation
Induction of mutations by radiation
is linearly related to exposure dose
Intercalating Agents
proflavin
acridine
ethidium
Intercalating Agents : Proflavin
REPAIR MECHANISM
Mechanism of post-replication mismatch correction
based on the methylation of the parental DNA strand
Excision Repair
- Excision Endonuclease
- Defect Binding Protein
- SSB
- DNA-Polymerase
- DNA Ligase
Excision repair of uracil in DNA
Excision repair of an apurinic or
apyrimidinic (AP) site
Repair of a damage site by
recombinational repair
-Between 2
damaged DNA
-Filling the
Gap with DNA
Ligase
-When
Excision
Repair fails
Restoration of the wild type phenotype by a second mutation
compensating for the first mutation : SUPPRESSOR MUTATION
SUPPRESSOR
MUTATION:
A mutation that
rescues another
mutation
Photoreactivation
DNA Mutation such as Pyrimidine
dimers introduced into DNA by UV
irradiation can be repaired by the
action of a single photoreactivating
enzyme using light in the range of
310–500 nm as an energy source.
Photolyases (EC 4.1. 99.3) are DNA
repair enzymes that repair damage
caused by exposure to ultraviolet
light. These enzymes require visible
light (from the violet/blue end of
the spectrum) both for their own
activation and for the actual DNA
repair.
THANK YOU FOR YOUR
ATTENTION
