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