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DNA repair is a mechanism according to which a cell is able to identify and correct damage to its DNA molecule that encodes its genome. In human metabolic activities as well as other factors such as chemicals, radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. While some cause mutations in cell's genome, which affects the successive generations of the cell. Overall we can say that DNA repair is an active process that constantly occurs as it responds to damage in DNA structure.
The rate of DNA repair is dependent on many factors such as:
1) Cell type
2) Age of cell
3) Extracellular environment etc.
. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
1. An irreversible state of dormancy, known as senescence.
2. Cell suicide, also known as apoptosis or programmed cell death.
3. Unregulated cell division, which can lead to the formation of a tumour that is cancerous.
The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection. Failure to correct molecular lesions in cells that form gametes can introduce mutations into the genomes of the offspring and thus influence the rate of evolution.
What is DNA damage?
DNA damage is the state according to which environmental factors and some other causes effect normal functioning of the cell due to its affected DNA structure. The vast majority of DNA damages affect the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, super coiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
SOURCES OF DNA DAMAGE
DNA damage can be subdivided in to two types
1) ENDOGENOUS DAMAGE.
2) EXOGENOUS DAMAGE.
Damage such as attack by reactive species group produced from normal metabolic by-product (spontaneous mutation), especially the process of oxidative deamination;
1) also includes replication errors
Damage caused by external agents such as:
1) ultraviolet rays from sun
2) other rays: X-rays, gamma rays
3) plant toxins
4) chemotherapy, radiotherapy
5) human made mutagenic chemicals, specially aromatic compounds.
DNA REPAIR MECHANISM
Basically it includes three types of mechanisms.
1) Base excision mechanism.
2) Nuclear excision mechanism.
3) Mis-match repair.
BASE EXCISION MECHANISM
Basically base excision repair mechanism is a cellular mechanism that repairs damaged DNA throughout the cell cycle. It is responsible for removing small, non helix distorting base lesions from genome .It is important for removing damaged bases that could cause mutation if not mended, by leading to mispairing or it can lead to breaks in DNA during replication.
BER is initiated by DNA glycolases, the function of DNA glycolases is to recognize and remove specific damaged bases from AP sites. These are then cleaved by AP endonuclease. The resulting single strand break can then be processed by either short patch or long patch BER.
CHOICE BETWEEN LONG PATCH AND SHORT PATCH REPAIR
The choice between short and long patch repair is currently under investigation. Various factors are thought to influence this decision, including the type of lesion, the cell cycle stage, and whether the cell is terminally differentiated or actively dividing. Some lesion, such as oxidized or reduced AP sites, are resistant to pol ß lyase activity and therefore must be processed by long-patch BER.
Pathway preference may differ between organisms, as well. While human cells utilize both short- and long-patch BER, there are certain organisms which can only use specified mechanism either long patch or short patch.
PROTEINS INVOLVED IN THE MECHANISM:
DNA GLYCOLASES: responsible for initial recognition of the lesion
AP ENDONUCLEASE: The AP endonucleases cleave an AP site to yield a 3' hydroxyl adjacent to a 5' deoxyribosephosphate
END PROCESSING ENZYME: In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5'end. In humans, polynucleotide kinase-phosphatase promotes formation of these ends during BER. This protein has a kinase domain, which phosphorylates 5' hydroxyl ends, and a phosphatase domain, which removes phosphates from 3' ends. Together, these activities ready single-strand breaks with damaged termini for ligation
DNA POLLYMERASES: Pol ß is the main human polymerase that catalyzes short-patch BER, with pol ? able to compensate in its absence. These polymerases are members of the Pol X family and typically insert only a single nucleotide. In addition to polymerase activity, these enzymes have a lyase domain which removes the 5' dRP left behind by AP endonuclease cleavage. During long-patch BER, DNA synthesis is thought to be mediated by pol d and pol e along with the processivity factor PCNA, the same polymerases that carry out DNA replication.
DNA LIGASE: DNA ligase I ligates the break in long patch BER.
NUCLEOTIDE EXCISIONN REPAIR:
Nucleotide excision repair mechanism is a DNA repair mechanism. As we know DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources such as chemicals but also ultraviolet (UV) light from the sun. Nucleotide excision repair (NER) is a particularly important mechanism by which the cell can prevent unwanted mutations by removing the vast majority of UV-induced DNA damage (mostly in the form of thymine dimmer and 6-4-photoproducts). The importance of this repair mechanism is evidenced by the severe human diseases that result from in-born genetic mutations of NER proteins including Xeroderma pigmentosum and Cockayne's syndrome.
The base excision repair machinery can recognize specific lesions in the DNA it can correct only damaged bases that can be removed by a specific glycosylase, the nucleotide excision repair enzymes recognize bulky distortions in the shape of the DNA double helix. Recognition of these distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled in by DNA polymerase, which uses the undamaged strand as a template. NER can be divided into two subpathways that differ only in their recognition of helix-distorting DNA damage.
These sub pathways are as:
1) Globe genomic NER
2) Transcription coupled NER
In all organisms, NER involves the following steps:
1. Damage recognition
2. Binding of a multi-protein complex at the damaged site
3. Double incision of the damaged strand several nucleotides away from the damaged site, on both the 5' and 3' sides
4. Removal of the damage-containing oligonucleotide from between the two nicks
5. Filling in of the resulting gap by a DNA polymerase
MIS MATCH REPAIR MECHANISM:
BEYOND THESE THREE MECHANISMS SOME OTHER METHODS: