Revision Notes: Agents of DNA Damage
Due to normal metabolic processes and environmental factors, inside cell DNA damage occurs that create molecular lesions in the cell. If this damage remains unrepaired, that can lead to genetic mutations and may even become the cause of several diseases like cancer.
Various types of Damages that can be found in the cell include:
1. Oxidative Damage
2. Alkylation of Bases
3. Hydrolysis of bases
4. DNA cross-linking
5. Strand break
- In this type of damage, cellular stress and damage of DNA is done by reactive oxygen species; hydroxyl ion is the most active reactive oxygen species (ROS).
- ROS can be produced by UV and ionizing radiation and forms oxo guanine from guanine residue; 8 oxo-G is the most common lesion in DNA.
- Alkylating agents are the most common damaging factors found in the environment. These intercalate with DNA and introduce lesion(s) into base which can be cytotoxic, or mutagenic.
- These lesions block replication and other signalling activity which leads to apoptosis.
- Methylation is the commonest type of alkylation found in DNA, leading to formation of 7 methyl Guanine,3 methyl adenineo6-methylguanine.
- In this process, damage occurs in nitrogen and oxygen of DNA. Amongst alkylation, O- type alkylation is more mutagenic and N-type is more cytotoxic.
Base Loss or AP Site Formation
- Abasic site(s) also known as AP site (Apurinic/ Apyrimidic site), it is a particular location in the DNA which is formed spontaneously or due to DNA Damage wherein loss of bases occurs.
- Damage Caused By Chemicals
- Some Biologically Active Chemicals React with Dna and Form Covalent Linkage and Create Large Bulky Adducts, for Eg. Benzopyrene, Tobacco, Coal Tar Etc.
- These molecules start metabolic processes in cell and form epoxides and create bulky adducts with bases in DNA.
- If they remain unrepaired, create mutation in DNA.
DNA Crosslinking or Dimer Formation
- When various exogenous and endogenous agents react with any two nucleotide of DNA and form covalent link, crosslinking occurs.
- It can happen in both the same and opposite strand of DNA.
- These forms of crosslinking interfere with the DNA replication process and cellular metabolism, which may eventually lead to cell death.
- UV light is a primal agent that can cause crosslinking between two pyrimidine (mostly Thymine) residues.
- Generally, UV creates products such as cyclobutene pyrimidine dimer and 6-4 photoproducts. These dimers alter the structure of base pair, usually are repaired by the photolyase enzyme but if remain unrepaired, these lesions halt replication of DNA and cause cell death or skin cancer.
Strand Break of DNA
- In this type of damage, ionising radiation inserts break in DNA strand.
- This leads to transcriptional and replicational error and may trigger neoplasia, cancer and premature aging. Some chemicals which form cross-linkage with DNA may induce topoisomerase catalysis also which supports the breakage in DNA strands.
Fig. Model of Topoisomerase IIB (TOP2B)-mediated DNA Double-Strand Breaks During Transcription.
Top: In the uninduced state of transcription, Pol II is paused between +25 and +100 from the transcription start site. The pausing is attributed to different elements including pausing-stabilizing transcription factors, the +1 nucleosome, and DNA structure and torsion. Positive supercoiling ahead of Pol II may require the function of TOP2B.
Middle: Transcription activation induced by various stimuli activates TOP2B to resolve DNA torsion in the promoter and gene body.
Bottom: In this process, double-strand breaks could be formed from abortive catalysis of TOP2B, which occurs frequently in some genes. This may be responsible for DNA damage response signalling that has been observed in a number of stimulus-inducible genes in humans.
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