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Overview of DNA Repair

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As the repository of all genetic information, DNA is highly stable.

However, like any organic molecule, it is susceptible to a variety of changes that alter its base chemistry including heat, radiation, and oxidation by free radicals produced during cellular respiration.

Also present abundantly in the cell is water, and this can cause hydrolytic damage. There are two types of hydrolytic reactions that spontaneously damage DNA bases under physiological conditions.

The first, deamination, affects pyrimidine bases such as cytosine, and is defined by the loss of an amino group in the presence of water that converts the base into Uracil. The second is depurination, which is the loss of purine bases due to the cleavage of the bond between the base and deoxyribose - leaving an apurinic site in the DNA.

These different types of damage lead to random mutations, which can be very harmful, causing genome instability, cell death, or cancers, amongst other conditions. Thankfully, only a few of these mutations are retained during DNA replication due to the cell’s highly efficient repair mechanisms.

The double-stranded structure of DNA itself is particularly suitable for repair because it contains two separate copies of the genetic information in its two strands. This means that, when one strand is damaged, the complementary strand can be used as a template to restore the correct nucleotide sequence.

There are three common DNA repair mechanisms. The first, base excision repair, focuses on fixing endogenous DNA damage, such as the hydrolytic damage resulting in deamination or depurination. Nucleotide excision repair can fix damage caused by ultraviolet light or certain chemical carcinogens, and finally, mismatch repair fixes faulty base incorporation by DNA polymerase during replication which leads to incorrect base-pairing.

Overview

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In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.

Chemically modified genomic DNA can cause errors during transcription and translation into proteins. If the damaged DNA is not repaired before cell division, the genomic mutations can be transferred to the next generations of cells. Some of these mutations can lead to uncontrolled cell growth that develops into cancer.

The cell has developed robust systems to detect and repair DNA damage. DNA damage can be repaired by enzymes that can directly reverse the chemical change in a single reaction. For example, enzyme photolyase uses UV radiation to split thymine dimers by opening the cyclobutane moiety that holds the thymine dimer together.

Other forms of repair follow a multi-step process in which

Chemical modifications in the DNA are detected
Damaged base or region is removed
New DNA is synthesized

If the damage is beyond repair, the cell can either become senescent or undergo apoptosis. Senescence is a state in which the cell becomes irreversibly dormant, i.e., it can no longer undergo cell division, and its cell cycle is halted indefinitely. Apoptosis refers to programmed cell death, where proteins called caspases degrade the cellular components required for cell survival. This is followed by the digestion of DNA by DNases, which causes the cell to shrink in size and transmit signals to a group of white blood cells called macrophages, which engulf and remove cellular debris.

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Base Excision Repair

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DNA Damage Detection

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