Download MUTATION, DNA REPAIR AND CANCER

MUTATION, DNA REPAIR AND CANCER
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Mutation
A heritable change in the genetic material
Essential to the continuity of life
Source
of variation for natural selection
New mutations are more likely to be
harmful than beneficial
DNA repair systems reverse DNA damage
Cancer is a disease caused by gene
mutations
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Gene mutations alter the DNA sequence
Point mutation affects only a single base
pair
2 basic alterations
1.
2.
Change base sequence
Add or remove nucleotide(s)
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Examples
Change base sequence
Base
substitution
5’ – CCCGCTAGATA – 3’
→
3’ – GGGCGARCTAT – 5’
5’ – CCCGCGAGATA – 3’
3’ – GGGCGCTCTAT – 5’
Add or remove a single base pair
5’ – GGCGCTAGATC – 3’
3’ – CCGCGATCTAG – 5’
→
5’ – GGCAGCTAGATC – 3’
3’ – CCGTCGATCTAG – 5’
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Gene mutations may affect amino acid sequences
Silent or neutral mutations
Do
not alter the amino acid sequence
Genetic code is degenerate
Missense mutation
Changes
a single amino acid in a polypeptide
May be neutral if substituted amino acid
similar in chemistry to original
Sickle-cell anemia is the result of a single
amino acid substitution
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Nonsense mutation
Change
from a normal codon to a stop or
termination codon
Produces a truncated polypeptide
Frameshift mutation
Addition
or deletion of nucleotides that are not
multiples of 3
Completely different amino acid sequence
downstream from mutation
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Gene mutations outside of coding sequences
Promoter
Up
promoter mutations or down promoter
mutations
Transcriptional response element/
operator site
May
alter regulation of transcription
Splice junctions
Mutations
at the boundaries between introns
and exons can prevent proper splicing
Translational response elements
May
prevent proper translational regulation
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Germ-line or somatic cell mutations
Exact time and location of a mutation is
critical to severity of effect and to the
ability to pass on the mutation
Germ-line cells give rise to gametes
Can
occur in a sperm or egg cell or in cell that
gives rise to eggs and sperm
Somatic cells are all other body cells
Can
occur early or late in development
Genetic mosaic results from patches of mutated
tissue
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Spontaneous or induced mutations
Spontaneous mutations result from
abnormalities in biological processes
Rates vary from species to species and
from gene to gene
Expected rate of background mutation
approximately 1 mutation for every 1
million genes
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Induced mutations are brought on by
environmental agents
Mutation rate higher than spontaneous
mutation rate
Mutagens are chemical or physical agents
Can
alter DNA in various ways
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DNA repair
All living organisms must have the ability
to repair changes that occur in DNA in
order to minimize mutation
Requires…
DNA
damage be detected
Repair of DNA damage
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Types of repair
Direct repair
Enzyme
removes a modification (for example
an alkyl group)
Altered DNA strand removed and new
segment synthesized
More
common
Nucleotide excision repair
Methyl-directed mismatch repair
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Nucleotide Excision Repair (NER)
Most common DNA repair system
Region encompassing several nucleotides
in the damaged strand is removed from
the DNA
Found in all eukaryotes. Intact
undamaged strand is used as a template
for resynthesis of a normal complementary
strand
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Methyl-directed mismatch repair system
Base mismatch is an abnormality where
the AT/GC rule not obeyed
DNA polymerase may make a mistake
May
correct itself with proofreading ability
Methyl-directed mismatch repair systems
exist in all species
Detect mismatch and specifically remove
segment from newly made strand
Specifically repairs the new strand rather
than the parental template strand
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Cancer
Disease of multicellular organisms that is
characterized by uncontrolled cell division
Over 1 million Americans are diagnosed
with cancer each year, and about half that
number will die from the disease
In about 10% of cancers, a higher
predisposition to develop the disease is an
inherited trait
Most cancers, about 90%, do not involve
genetic changes that are passed from
parent to offspring
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Carcinogens
About 80% of all human cancers are
related to exposure to carcinogens
Agents that increase the likelihood of
developing cancer
Most carcinogens, such as UV light and
certain chemicals in cigarette smoke, are
mutagens that promote genetic changes in
somatic cells
DNA alterations can lead to effects on
gene expression that ultimately affect cell
division, and thereby lead to cancer
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Cancers originate from a single cell
Mutates so that cell grows abnormally
Tumor- an overgrowth of cells with no
useful purpose
Tumor may begin as a benign or precancerous
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Cancerous stage
Malignant
- lost normal growth regulation
Invasive- can invade healthy tissue
Metastatic- can migrate to other parts of the
body
Left untreated, malignant cells will cause
the death of the organism
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Cancer-causing genes
Oncogene
When
a mutation causes this gene to be
overactive, uncontrolled cell growth occurs.
Tumor-suppressor gene
Normally,
this gene encodes a protein that
prevents cancer
If a mutation eliminates this function, cancer
can occur
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Oncogenes
Cell division regulated by hormones called growth
factors
Bind to cell surface and initiate cascade leading to cell
division which includes activating specific genes
Mutations in genes producing cell growth signaling
proteins can change them into oncogenes producing
abnormally high level of activity in some proteins
An oncogene may promote cancer by keeping the cell
division signaling pathway in a permanent “on” position
In some cancers the amount of gene product is abnormally high
In others the gene produces a functionally hyperactive protein
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Proto-oncogene
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2.
3.
4.
Normal gene that, if mutated, can
become an oncogene
4 common genetic changes
Missense mutations
Gene amplifications
Chromosomal translocations
Retroviral insertions
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Missense mutations
Chemical mutagens have been shown to
cause missense mutations leading to cancer
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Gene
amplifications
Abnormal
increase in copy
number results in
too much of the
encoded protein
Many human
cancers are
associated with
the amplification
of particular protooncogenes
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Chromosomal
translocations
Two
different
chromosomes break,
and the ends of the
broken chromosomes
fuse with each other
incorrectly
Very specific types of
chromosomal
translocations have been
identified in certain types
of tumors
Chimeric genes are
composed of two gene
fragments fused together
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Retroviral insertions
Viral DNA may insert into
a host chromosome in
such a way that a viral
promoter and response
elements are next to a
proto-oncogene
May result in the
overexpression of the
proto-oncogene,
thereby promoting
cancer
Alternatively, a virus may
cause cancer because it
carries an oncogene in the
viral genome
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