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Three different types of excision repair have been characterized: nucleotide excision repair, base excision repair, and mismatch repair.
All utilize a cut, copy, and paste mechanism. In the cutting stage, an enzyme or complex removes a damaged base or a string of nucleotides from the DNA. The DNA polymerase can initiate synthesis from 3' OH at t he single-strand break nick or gap in the DNA remaining at the site of damage after excision.
In nucleotide excision repair , damaged bases are cut out within a string of nucleotides, and replaced with DNA as directed by the undamaged template strand. This repair system is used to remove pyrimidine dimers formed by UV radiation as well as nucleotides modified by bulky chemical adducts. The common feature of damage that is repaired by nucleotide excision is that the modified nucleotides cause a significant distortion in the DNA helix.
NER occurs in almost all organisms examined. The genes encoding this repair function were discovered as mutants that are highly sensitive to UV damage, indicating that the mutants are defective in UV repair. As illustrated in Figure 7.
Mutant strains can be identified that are substantially more sensitive to UV radiation; these are defective in the functions needed for UV - r esistance, abbreviated uvr. By collecting large numbers of such mutants and testing them for their ability to restore resistance to UV radiation in combination, complementation groups were identified. The enzymes encoded by the uvr genes have been studied in detail. It then cleaves on both sides of the damage.
Thus for this system, the UvrABC and UvrD proteins carry out a series of steps in the cutting phase of excision repair. The UvrABC proteins form a dynamic complex that recognizes damage and makes endonucleolytic cuts on both sides. The two cuts around the damage allow the single-stranded segment containing the damage to be excised by the helicase activity of UvrD.
After the damaged segment has been excised, a gap of 12 to 13 nucleotides remains in the DNA. In more detail, the process goes as follows Figure 7. UvrA 2 then dissociates, in a step that requires ATP hydrolysis. The UvrBC complex is the active nuclease.
It makes the incisions on each side of the damage, in another step that requires ATP. The phosphodiester backbone is cleaved 8 nucleotides to the 5' side of the damage and nucleotides on the 3' side. Like all helicase reactions, the unwinding requires ATP hydrolysis to disrupt the base pairs. Thus ATP hydrolysis is required at three steps of this series of reactions. Nucleotide excision repair is very active in mammalian cells, as well as cells from may other organisms.
The DNA of a normal skin cell exposed to sunlight would accumulate thousands of dimers per day if this repair process did not remove them! One human genetic disease, called xeroderma pigmentosum XP , is a skin disease caused by defect in enzymes that remove UV lesions. Fibroblasts isolated from individual XP patients are markedly sensitive to UV radiation when grown in culture, similar to the phenotype shown by E.
These XP cell lines can be fused in culture and tested for the ability to restore resistance to UV damage.
XP cells lines that do so fall into different complementation groups. Several complementation groups, or genes, have been defined in this way. Considerable progress has been made recently in identifying the proteins encoded by each XP gene Table 7. Note the tight analogy to bacterial functions needed for NER.
Similar functions are also found in yeast Table 7. NER occurs in two modes in many organisms, including bacteria, yeast and mammals. One is the global repair that acts throughout the genome, and the second is a specialized activity is that is coupled to transcription.
In transcription coupled NER, the elongating RNA polymerase stalls at a lesion on the template strand; perhaps this is the damage recognition activity for this mode of NER. A rare genetic disorder in humans, Cockayne syndrome CS , is associated with a defect specific to transcription coupled repair. Determination of the nature and activity of the proteins encoded by them will provide additional insight into the efficient repair of transcribed DNA strands.
The phenotype of CS patients is pleiotropic, showing both photosensitivity and severe neurological and other developmental disorders, including premature aging.
The mismatch repair proteins detect this base and remove it from the newly synthesized strand by nuclease action. The gap is now filled with the correctly paired base. Figure 3. Nucleotide excision repairs thymine dimers. When exposed to UV, thymines lying adjacent to each other can form thymine dimers. In normal cells, they are excised and replaced. Once the bases are filled in, the remaining gap is sealed with a phosphodiester linkage catalyzed by DNA ligase.
This repair mechanism is often employed when UV exposure causes the formation of pyrimidine dimers. Today, scientists suspect that most DNA replication errors are caused by mispairings of a different nature: either between different but nontautomeric chemical forms of bases e. This type of mispairing is known as wobble. It occurs because the DNA double helix is flexible and able to accommodate slightly misshaped pairings Crick, Figure 2: Wobble in mismatched nucleotide base pairs.
A shift in the position of nucleotides causes a wobble between a normal thymine and normal guanine. An additional proton on adenine causes a wobble in an adenine-cytosine base-pair. Genetics: A Conceptual Approach, 2nd ed. Replication errors can also involve insertions or deletions of nucleotide bases that occur during a process called strand slippage.
Sometimes, a newly synthesized strand loops out a bit, resulting in the addition of an extra nucleotide base Figure 3. Other times, the template strand loops out a bit, resulting in the omission, or deletion, of a nucleotide base in the newly synthesized, or primer , strand.
Regions of DNA containing many copies of small repeated sequences are particularly prone to this type of error. DNA polymerase enzymes are amazingly particular with respect to their choice of nucleotides during DNA synthesis, ensuring that the bases added to a growing strand are correctly paired with their complements on the template strand i.
Nonetheless, these enzymes do make mistakes at a rate of about 1 per every , nucleotides. That might not seem like much, until you consider how much DNA a cell has. In humans, with our 6 billion base pairs in each diploid cell, that would amount to about , mistakes every time a cell divides!
Fortunately, cells have evolved highly sophisticated means of fixing most, but not all, of those mistakes. Some of the mistakes are corrected immediately during replication through a process known as proofreading , and some are corrected after replication in a process called mismatch repair.
During proofreading, DNA polymerase enzymes recognize this and replace the incorrectly inserted nucleotide so that replication can continue.
After replication, mismatch repair reduces the final error rate even further. Incorrectly paired nucleotides cause deformities in the secondary structure of the final DNA molecule. During mismatch repair, enzymes recognize and fix these deformities by removing the incorrectly paired nucleotide and replacing it with the correct nucleotide. Incorrectly paired nucleotides that still remain following mismatch repair become permanent mutations after the next cell division.
This is because once such mistakes are established, the cell no longer recognizes them as errors. Consider the case of wobble-induced replication errors. When these mistakes are not corrected, the incorrectly sequenced DNA strand serves as a template for future replication events, causing all the base-pairings thereafter to be wrong.
For instance, in the lower half of Figure 2, the original strand had a C-G pair; then, during replication, cytosine C is incorrectly matched to adenine A because of wobble. In this example, wobble occurs because A has an extra hydrogen atom. In the next round of cell division, the double strand with the C-A pairing would separate during replication, each strand serving as a template for synthesis of a new DNA molecule.
At that particular spot, C would pair with G, forming a double helix with the same sequence as its original i. This type of mutation is known as a base, or base-pair, substitution. Base substitutions involving replacement of one purine for another or one pyrimidine for another e.
Likewise, when strand-slippage replication errors are not corrected, they become insertion and deletion mutations. Much of the early research on strand-slippage mutations was conducted by George Streisinger in the s. Streisinger, a professor at the University of Oregon and a fish hobbyist, is known by some as the "founding father of zebrafish research. Streisinger used this virus to show that most nucleotide insertion and deletion mutations occur in areas of DNA that contain many repeated sequences also called tandem repeats , and he formulated the strand-slippage hypothesis to explain why this was the case Streisinger et al.
In Figure 3, notice the series of repeat T's on the template strand where the slippage has occurred. When slippage takes place, the presence of nearby duplicate bases stabilizes the slippage so that replication can proceed. During the next round of replication, when the two strands separate, the insertion or deletion on either the template or primer strand, respectively, will be perpetuated as a permanent mutation.
Scientists have collected enough evidence to confirm Streisinger's strand-slippage hypothesis, and this type of mutagenesis remains an active field of scientific research. Figure 3: Strand slippage during DNA replication. When strand slippage occurs during DNA replication, a DNA strand may loop out, resulting in the addition or deletion of a nucleotide on the newly-synthesized strand.
Although most mutations are believed to be caused by replication errors, they can also be caused by various environmentally induced and spontaneous changes to DNA that occur prior to replication but are perpetuated in the same way as unfixed replication errors. As with replication errors, most environmentally induced DNA damage is repaired, resulting in fewer than 1 out of every 1, chemically induced lesions actually becoming permanent mutations.
The same is true of so-called spontaneous mutations.
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