Question

The mechanism of DNA repair describe in details (more than 1500 words)

Answer 1

DNA repair

• DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.
• In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage.
• Many of these lesions cause structural damage to the DNA molecule and can eliminate the cell's ability to transcribe the gene that the affected DNA encodes.
• Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis.
• As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure.
• When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages.
• This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Importance of DNA repair

• DNA repair ensures the survival of a species by enabling parental DNA to be inherited as faithfully as possible by offspring.
• It also preserves the health of an individual.
• Mutations in the genetic code can lead to cancer and other genetic diseases.

Mechanism of DNA repair

There are two general classes of DNA repair

• Direct reversal of the chemical process generating the damage
• The replacement of damaged nucleotide bases.

DNA encodes the cell genome and is therefore a permanent copy of a structure necessary for the correct functioning of a cell. Changes to the structure of DNA can cause mutations and genomic instability, leading to cancer. Damage to DNA is caused by the incorporation of incorrect nucleotide bases during DNA replication and the chemical changes caused by spontaneous mutation or exposure to environmental factors such as radiation.

Direct reversal DNA repair mechanism

Direct reversal through photoreactivation can inverse this dimerization reaction by utilizing light energy for the destruction of the abnormal covalent bond between adjacent pyrimidine bases. This type of photoreactivation does not occur in humans.

• The damage caused by alkylating agents reacting with DNA can also be repaired through direct reversal.
• Methylation of guanine bases produces a change in the structure of DNA by forming a product that is complimentary to thymine rather than cytosine.
• The protein methyl guanine methyl transferase can restore the original guanine by transferring the methylation product to its active site.

DNA repair by excision

Excision is the general mechanism by which repairs are made when one of the double helix strands is damaged. The non-defective strand is used as a template with the damaged DNA on the other strand removed and replaced by the synthesis of new nucleotides. There are three types of excision repair:

1. Base-excision repair.
2. Nucleotide excision repair.
3. Mismatch repair.

Base - excision repair

• It involves the recognition and removal of a single damaged base.
• The mechanism requires a family of enzymes called glycosylases.
• The enzymes remove the damaged base forming an AP site which is repaired by AP endonuclease before the nucleotide gap in the DNA strand is filled by DNA polymerase.

Nucleotide-excision repair

• Nucleotide excision repair is a widespread mechanism for repairing damage to DNA and recognizes multiple damaged bases.
• This mechanism is used to repair the formation of pyrimidine dimers from UV light within humans.
• The process involves the recognition of damage which is then cleaved on both sides by endonucleases before resynthesis by DNA polymerase.

Mismatch repair

• Mismatch repair occurs when mismatched bases are incorporated into the DNA strand during replication and are not removed by proofreading DNA polymerase.
• In mismatch repair, the missed errors are later corrected by enzymes which recognize and excise the mismatched base to restore the original sequence.

DNA double strand break repair

The repair of damage to both DNA strands is particularly important in maintaining genomic integrity. There are two main mechanisms for repairing double strand breaks:

• Homologous recombination
• Classical nonhomologous end joining.

Homologous recombination

• Homologous recombination involves the exchange of nucleotide sequences to repair damaged bases on both strands of DNA through the utilization of a sister chromatid.

Classical nonhomologous end joining

• Classical nonhomologous end joining connects the break ends without a homologous template through the use of short DNA sequences called microhomologies.
• The mechanism is prone to error but protects genome integrity from possible chromosomal translocations that can occur through homologous recombination.