Download A16Cancer

Chapter 17
Altering the genetic message:
Mutation
Cancer.
MUTATIONS
= change in the genetic message
= change in the nucleotide sequence of a gene
= DNA Damage + DNA Repair.
1. Types of mutations
2. Causes of DNA damage
3. DNA (damage) repair
Types of mutations.
A. Gene mutations
a. point mutations
or base-pair substitution
b. frame-shift mutations
B. Chromosomal mutations
(duplication, inversion, deletion,
translocation)
Causes of DNA damage.
1. Spontaneous
(tautomeric shift, deamination,
depurination, looping-out)
2. Oxidation
3. Chemical
- base-pair analogs
- base-modifying agents
- intercalating agents
- agents that cause ‘bulky’ lesions
4. Physical: - UV light
- X-ray
Causes of DNA damage.
1. Spontaneous
- tautomeric shift
- deamination
- depurination
- strand slippage/looping-out
Tautomeric shift of bases
Common Form
Uncommon Form
Tautomeric shift leads to altered base pairing.
Depurination of
DNA
Apurinic sites
De-amination of cytosine or methyl-cytosine.
Strand slippage during DNA replication
5’TACGGAC 3’
3’ATGCCTGACTTTGC 5’
Newly synthesized DNA
Template DNA
T
5’TACGGACTG 3’
3’ATGCCTGACTTTGC 5’
Newly synthesized DNA
loops out, …
T
5’TACGGACTGAAACG 3’
3’ATGCCTGACTTTGC 5’
… resulting in the
addition of one
nucleotide in the new
strand.
Strand slippage during DNA replication
5’TACGGAC 3’
3’ATGCCTGACTTTGC 5’
Newly synthesized DNA
Template DNA
5’TACGGACTG 3’
3’ATGCCTGCTTTGC 5’
A
Template DNA loops
out, …
5’TACGGACGAAACG 3’
3’ATGCCTGCTTTGC 5’
A
… resulting in the
omission of one
nucleotide in the new
strand.
Causes of DNA Damage
2. Oxidative damage
(Respiration, Mixed function oxidases, Inflammation)
Causes of DNA damage.
3. Physical
UV-Light
(254 – 260 nm)
Pyrimidine
dimers
Gross distortion
DNA molecule
Malignant Melanoma
Causes of DNA damage.
3. Physical
Causes of DNA damage.
4. Chemical
- base-pair analogs
- base-modifying agents
- alkylating agents
- base deaminating
- intercalating agents
- agents that cause ‘bulky’ additions
Causes of DNA
damage
4. Chemical:
Base Analogs
Miss-pairing
Alkylating agents add alkyl groups
 Cause altered base pairing
E.g., Ethyl-methane-sulfonate (mustard gas),
Nitroso-guanidine.
Base deamination
E.g., nitrous acid, bisulfite
Actinomycin
Ethidium Bromide
Acriding Orange
Tetracycline
Proflavine
Intercalating agents
Bulky additions
grossly distort the
DNA
Aflatoxins
… ‘bulky’ additions,
gross distortions of
the DNA
Benzo (a) pyrene
Cellular Responses to DNA damage
Error-free
DNA repair
Apoptosis
Error-prone DNA repair
Mutation
DNA Repair:
1. Direct correction of DNA repair
a. Proofreading of DNA polymerase
b. Repair of alkylating damage
2. Repair involving excission of base pairs
a. General excission repair system (UvABC)
b. Repair by glycosylases and
AP endonucleases
c. Mismatch-repair system
d. SOS-repair system
Proofreading Capacity of DNA Polymerase
Repair by Alkyl-transferases
General Excision repair system
Xeroderma
pigmentosa:
Deficiency of the
general excision
repair system.
Glycosylase/
AP endonuclease
Repair system
Repair by DNA glycosylase
and AP endonucleases.
Mismatch
Repair System
Hereditary Non-Polyposus Colonrectal Cancer (HNPCC)
Error-prone
repair by
end-joining.
Chapter 17
Altering the genetic message:
Cancer.
Independent of
growth signals
Tissue invasion
metastasis
Insensitive to
growth inhibitors
Sustained
angiogenesis
Cancer
Changed energy
metabolism
Limitless replicative
potential
Avoid apoptosis
Normal cells
Cancer cells loose contact inhibition,
grow on top of each other, and become
rounded.
Normal
Cancer
Normal
(contact
inhibition)
Cancer
Rous sarcoma virus
Nobel Prize 1989
Chicken Rous Sarcoma Virus (RSV) carried an oncogene
called v-src and this gene was an intronless version of a
normal chicken gene called c-src.
DNA Damage
+
DNA Repair
Active
tumor suppressor
gene(s)
Proto-oncogene(s)
MUTATIONS
Oncogene(s)
Inactive
tumor suppressor
gene(s)
Gain-of-function
Dominant
phenotype
Loss-of-function
CANCER
Recessive
phenotype
Retinoblastoma.
EF2
Rb
Cdk2-cyclin E
P
+
DNA
mRNA
DNA polymerase
S-phase
CANCER:
A multi-hit process of mutations
accumulating in proto-oncogenes
and tumor suppressor genes.
Familial Adenomatous Polyposis Coli
Colonoscopy Results
JB Weitzmann and Nosh Yaniv
Nature 1999, 400 p401
What causes cancer?
1. Environmental carcinogens
- chemical (e.g., cigarette smoke)
- physical (e.g., UV radiation)
2. Host carcinogens (e.g., inflammation)
3. Viruses:
TUMOR VIRUSES
Papiloma virus
Hepatitis B virus
Human Herpes virus 8 (Kaposi)
Human Herpes virus 4 (Epstein Bar)
Human T lymphotropic virus
This woman has
hepatitis B and is
suffering from liver
cancer. She was a
Cambodian refugee
and died 4 months
after she arrived in a
refugee camp
(average life
expectancy after
diagnosis of liver
cancer is 6 months)
Kaposi syndrome: Human Herpes Virus 8)
Cutaneous B cell
lymphoma
HTLV
Leukemia
The End.