Oncology – Chapter 2 DNA structure and stability: mutations
versus repair
PART 1
DNA and cancer
DNA
4 bases;
• Purines
o Adenine (2 hydrogenbond)
o Guanine (3 hydrogenbond)
• Pyrimidines
o Cytosine (3 hydrogenbond)
o Thymine (2 hydrogenbond)
o Uracil (only in RNA)
Base = base (Adenine)
Base + sugar = nucleoside (Adenosine, cytidine, guanosine, thymidine)
Base + sugar + phosphate = nucleotide (AMP, ADP, ATP)
1’ base
2’ H
3’ OH (hydroxyl group)
4’ H
5’ phosphate group
5’ end = phosphate (phosphate group)
3’ end = sugar (hydroxyl group)
From 5’ → 3’
The double helix
2 chains running in opposite direction.
A-T and G-C base pairs is complementary.
This complementary base pairing makes DNA a suitable
molecule for carrying our genetic information. One template
that copied the DNA readily and passes on to the next
generation.
RNA
RNA has U instead of T
RNA has at 2’ OH instead of H
RNA is mostly a single-stranded molecule.
From DNA to proteins
Transcription; DNA → RNA – takes place in nucleus
Between this splicing take place; remove introns
Translation; RNA → proteins – takes place on ribosomes in
the cytoplasm
, 2 parts in a gene
1. Promotor region; located at 5’ end; involved in regulating the
expression. Response element (RE) lies within the promotor
region and contributes to the regulation.
TATA box is located near the start of the transcription. Binding of
the TAT box binding protein (TBP) to TAT box is crucial for initiation of transcription
2. Coding region
Enhancer elements are additional regulatory DNA sequences that are positioned and
orientated independent relative to a promotor.
Super-enhancers are clusters of enhancer elements.
Genetic stability/instability
Genetic stability:
DNA damage → intact DNA by repairing
Genetic instability:
Intact DNA → DNA damage → DNA mutations → change of cell
function (cancer)
Mutations
• In exon region: result in mutated proteins
• In exon-intron boundaries: result in altered splicing
• In deep-intronic: also have consequences for the splicing
process
• In promotor region: functional consequences like increased
or reduced expression of genes
• Mutation far from the transcriptional start: may also have functional
consequences
Drivers for oncogenesis:
- Cancer genes:
1. Stability genes: function in DNA repair pathways – inactivation of DNA repair
result in more DNA mutations
2. Oncogenes: activation can aid tumorigenesis – activation can be achieved by
mutation of the protein or enhanced expression
3. Tumor suppressor genes: inactivation can aid tumorigenesis – inactivation can
be achieved by mutation of the protein or reduced expression
- Epigenetic mutations
- Viral infections; viral proteins interact with cellular cancer proteins such as
TP53 or RB1
Changes in DNA
• Small DNA changes
o Base pair substitutions: transition (substitution of one
purine for another purine) + transversion (substitution
of a purine for a pyrimidine or vice versa)
versus repair
PART 1
DNA and cancer
DNA
4 bases;
• Purines
o Adenine (2 hydrogenbond)
o Guanine (3 hydrogenbond)
• Pyrimidines
o Cytosine (3 hydrogenbond)
o Thymine (2 hydrogenbond)
o Uracil (only in RNA)
Base = base (Adenine)
Base + sugar = nucleoside (Adenosine, cytidine, guanosine, thymidine)
Base + sugar + phosphate = nucleotide (AMP, ADP, ATP)
1’ base
2’ H
3’ OH (hydroxyl group)
4’ H
5’ phosphate group
5’ end = phosphate (phosphate group)
3’ end = sugar (hydroxyl group)
From 5’ → 3’
The double helix
2 chains running in opposite direction.
A-T and G-C base pairs is complementary.
This complementary base pairing makes DNA a suitable
molecule for carrying our genetic information. One template
that copied the DNA readily and passes on to the next
generation.
RNA
RNA has U instead of T
RNA has at 2’ OH instead of H
RNA is mostly a single-stranded molecule.
From DNA to proteins
Transcription; DNA → RNA – takes place in nucleus
Between this splicing take place; remove introns
Translation; RNA → proteins – takes place on ribosomes in
the cytoplasm
, 2 parts in a gene
1. Promotor region; located at 5’ end; involved in regulating the
expression. Response element (RE) lies within the promotor
region and contributes to the regulation.
TATA box is located near the start of the transcription. Binding of
the TAT box binding protein (TBP) to TAT box is crucial for initiation of transcription
2. Coding region
Enhancer elements are additional regulatory DNA sequences that are positioned and
orientated independent relative to a promotor.
Super-enhancers are clusters of enhancer elements.
Genetic stability/instability
Genetic stability:
DNA damage → intact DNA by repairing
Genetic instability:
Intact DNA → DNA damage → DNA mutations → change of cell
function (cancer)
Mutations
• In exon region: result in mutated proteins
• In exon-intron boundaries: result in altered splicing
• In deep-intronic: also have consequences for the splicing
process
• In promotor region: functional consequences like increased
or reduced expression of genes
• Mutation far from the transcriptional start: may also have functional
consequences
Drivers for oncogenesis:
- Cancer genes:
1. Stability genes: function in DNA repair pathways – inactivation of DNA repair
result in more DNA mutations
2. Oncogenes: activation can aid tumorigenesis – activation can be achieved by
mutation of the protein or enhanced expression
3. Tumor suppressor genes: inactivation can aid tumorigenesis – inactivation can
be achieved by mutation of the protein or reduced expression
- Epigenetic mutations
- Viral infections; viral proteins interact with cellular cancer proteins such as
TP53 or RB1
Changes in DNA
• Small DNA changes
o Base pair substitutions: transition (substitution of one
purine for another purine) + transversion (substitution
of a purine for a pyrimidine or vice versa)
