Lecture notes
DNA STRUCTURE
- Module
- Mechanisms of pathology
- Institution
- Aston University, Birmingham (Aston)
Lecture notes of 10 pages for the course Mechanisms of pathology at Aston (IMMUNOLOGY NOTES)
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DNA STRUCTURE REVISIION.Section 1: revision on nucleic acid bases and nucleic acid structure.
The structure of bases:
adenine (adenosine): consists of 1 hydrogen donor for hydrogen bonding and 1
acceptor in hydrogen bonding. This is a purine.
Thymine (thymidine): consists of 1 acceptor in hydrogen bonding and 1 hydrogen
donor in hydrogen bonding. This is a pyrimidine.
Guanine (guanosine): consists of 1 acceptor in hydrogen bonding and 2 hydrogen
donors in hydrogen bonding. This is a purine
Cytosine (cytidine): this consists of 1 hydrogen donor in hydrogen bonding. And 2
acceptors in hydrogen bonding. This is a pyrimidine.
Cytosine and guanine interactions involve 3 hydrogen bonds whereas adenine and
thymine interactions involve 2 hydrogen bonds.
DNA and RNA polymers:
RNA is usually found in the cell as single strand, sometimes folded into a specific
shape.
DNA exists for most of the time in the cell in a double stranded form i.e. two
polynucleotides strands held together by non-covalent bonds.
This is the double helix model and has the following features:
The two polynucleotide strands run in opposite directions (anti-parallel strands).
The sugar-phosphate-sugar backbone is on the outside, and the bases on the inside.
The two strands are held together by hydrogen bonding between pairs of bases
(base pairs) on opposite strands.
The two anti-parallel strands are twisted to form a right handed helix with about 10
base-pairs per turn.
DNA and RNA can be easily damaged: DNA is so precious and fragile that the cell has
a whole variety of repair mechanisms to protect its DNA from assaults by radiation,
chemicals and other hazards.
Section 2: mechanisms of physical, chemical and biological damage to DNA.
Overview of types of DNA damage.
Can be divided into strand breaks and nitrogen base damage.
Strand breaks- at the level of the polymer: they may occur by breaking bonds at
sugar or phosphate. This is breaking of the chemical bonds that hold the polymer
together. The polymer is a continuous strand of sugar, phosphate, sugar phosphate.
This is the back bone.
The back bone of each of the two strands of DNA are anti parallel strands.
Single strand breaks (SSB)- there is a break in one of the nucleic acid polymer chains.
Double strand breaks (DSB)- both of the polymers are cleaved, so the bonds are
broken. This means that this part is no longer connected to the rest of the double
helix. Double strand breaks are the most serious types of damage.
, Nitrogen base damage- causes changes in the base structure but may not break the
polymer. The nitrogen bases in the centre are also susceptible to damage. Nitrogen
is readily oxidised, and amine groups can be readily modified. The nitrogen base
damage causes damage to the base structures, so therefore it may affect its base
pairing. However, it usually does not break the polymer.
The bases can get oxidised, so there is an addition of oxygen.
Bases can be alkylated, so hydrocarbon groups of various kinds are added to it, like
an acetyl group would be alkylation.
Hydroxylation is when an OH is added.
Oxidation of bases alkylation of bases hydroxylation of bases
Cross-linking between bases, so covalent bonds can be directly formed between the
bases.
Crosslinking between bases and proteins in chromatin.
Overview of types of agents that damage DNA.
Physical agents: ionising radiation (x-rays, radioactivity) , ultraviolet radiation.
Chemical agents: alkylating agents (methyl bromide) these can cause modification of
bases, cigarette smoke and tar products (including radicals) these are oxidising,
toxins from fungi produce aflatoxin this is very reactive and can modify DNA,
deaminating agents these remove amino groups, intercalating agents, these slip in
between the bases and cause problems, ethidium bromide can be used to visualise
DNA because of its strong binding within the double helix.
Normal physiological agents: (biological agents): these compounds exist normally in
biological systems: mitochondrial metabolism, through the process of electron
transport, electrons can escape and get onto oxygen and this generates reactive
oxygen species (reactive oxygen species-ROS) and respiratory burst of macrophages
and neutrophils produce reactive oxygen species ect. (ROS,RNS, free radicals).
DNA damage by ionizing radiation (IR).
Ionizing radiation includes X rays, gamma rays, beta particles (high speed electrons),
alpha particles (the nucleus of the helium atom).
These all have very high energy and can break covalent bonds in DNA or nearby
molecules.
Radiation damage can interfere with the hydrogen bonds, it can cause double strand
breaks, which are the most serious lesions, it can cause pyrimidine dimers, dimers
between two thymine’s or two cytosines or between thymine and cytosine. It is
usually formed between adjacent bases.
DNA cross links can be formed, so covalent bonds between the two bases that are
supposed to be base paired, they can become covalently linked.
Bases can be lost from the sugar phosphate backbone, and the bases can be
changes. Eg. Thymine to uracil.
There can be single strand breaks as well as cross-links to protein.
The action can be direct by the ionising radiation on the DNA or indirect by 1 st
forming radicals from water, which then reacts with DNA and causes damage.
X rays and gamma rays are electromagnetic waves, like light, but their energy is
much higher than that of light (their wavelengths are much shorter).
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