DNA DAMAGE AND REPAIR
Requirements of Homologous Recombination
(1) DNA duplexes that are similar or identical in nucleotide sequence (homology). (2) is initiated when a double-strand break occurs immediately after DNA has been replicated (3) the duplicated helices are still in close proximity to one another
Chemical Modifications of Nucleotides
1- Depurination 2- Deamination 3- covalent linkage
Methods of Repair of Double-Strand Breaks
1- Nonhomologous end-joining repair 2- Homologous Recombination
Basic mechanism of repairing DNA
1- Remove damaged region 2- Resynthesis DNA 3- Ligate
Advantages of Homologous Recombination
1- Uses the genetic information in undamaged DNA duplex as a template to accurately repair a broken DNA double helix 2- Error-free repaired double-strand breaks 3- It can repair many other types of DNA damage, making it perhaps the most versatile DNA repair mechanism available to the cell.
Disadvantage of Nonhomologous end-joining repair
1. no intact template strand to guide proper repair 2. double-Strand Breaks Can be Repaired Rapidly But Imperfectly 3. Nucleotides are lost at the site of repair, which may lead to: i) Loss the information contained at the site of the injury ii) be a mutagenic. iii) Predispose to cancer and immunodeficiency syndromes.
Mutation in a "germ cell"
A Mutation that will be passed to all the cells in the body of the multicellular organism and inherited to the next generation
Mutation in a "Somatic cell"
A Mutation that will give rise to "Variant cells", some of which grow and divide in an uncontrolled fashion at the expense of the other cells causing "Cancer"
Double-Strand Breaks
may lead quickly to the fragmentation of chromosomes which, If unrepaired, cause a loss of genes during cell divides
Advantage of Nonhomologous end-joining repair
simple and common, Does not require sequence homology in the two DNA fragments
Effects of unrepaired Chemical Modifications of Nucleotides IN DNA
would lead either to: 1- the substitution of one nucleotide pair for another as a result of incorrect base pairing during replication 2- deletion of one or more nucleotide pairs in the daughter DNA strand after DNA replication. 3- Thymine dimers often stall the DNA replication
Ligate
DNA ligase seals the nick left in the sugar-phosphate backbone of the repaired strand
DNA Repair Mechanisms
DNA mismatch repair, nucleotide excision repair, and DNA double strand break repair
Resynthesis DNA
Filling the gap by synthesizing a correct sequences catalyzed by DNA polymerase by using the sister undamaged strand.
Risk of uncorrected DNA Mismatch
Inherited mutations in genes that encode mismatch repair proteins may cause certain cancers
Causes of Double-Strand Breaks
Ionizing radiation, Mishaps at the replication fork, Radioactive disintegration of backbone element, Strong oxidizing agents, Active Metabolites produced in the cell
Remove damaged region
The damaged DNA is cut out by one of nucleases and Removed (i.e. excised) damage leaving a small gap on one strand of the DNA double helix
Clinical Effect of Thymine Dimers (covalent linkage)
Xeroderma Pigmentosum
DNA damage
Missing base, Altered base, Incorrect base
DNA Mismatch Repair
Removes and corrects Replication Errors (e.g. Mismatched or mispaired Nucleotides) That Escape the Replication Machine
Results of Xeroderma Pigmentosum
Severe skin lesions, including skin cancer because of the accumulation of thymine dimers in cells that are exposed to sunlight
Xeroderma Pigmentosum
A malignant condition and an Autosomal recessive disease
Cause of Xeroderma Pigmentosum
Defect in NER
Depurination
The removal of purine base from nucleotides
Nonhomologous end-joining repair
The two broken ends are brought together by specific enzymes and rejoining by DNA ligation
covalent linkage
UV Radiation promotes it between two adjacent pyrimidine bases, forming thymine-thymine dimer (prevent DNA replication)
Deamination
spontaneous loss of an amino group which turns Cytosine to Uracil and Adenine to Hypoxanthine