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Replacing, instead of repairing, DNA

Replacing, instead of repairing, DNA


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I've been doing some light reading on DNA damage theory of aging. One of the main ideas from that theory that I got is that the accumulation of damage in our DNA is one of the biggest causes of why we age, which is quite intuitive for a non-biology major like me. Furthermore, there has been research on DNA damage repair pathways and ways on how nanotech can help repair DNA. The technicalities are beyond me. My question is

If accurate DNA repair is such a difficult mechanism to sustain over a lifespan, then why not catabolize DNA and replace it with a new one?

It seems very feasible to synthesize human DNA (please inform my ignorance, if I'm wrong. lol.) and it looks very promising after reading this: https://www.wired.com/story/live-forever-synthetic-human-genome/.

EDIT: It was pointed out to me in the comments that my question is too broad, please do tell me how to make it more specific, if you agree that's the case here. I'm very happy to accept technical answers, since I can always retrace it to the basics.


It seems very feasible to synthesize human DNA (please inform my ignorance, if I'm wrong. lol.) and it looks very promising after reading this: https://www.wired.com/story/live-forever-synthetic-human-genome/.

It is certainly possible to synthesize human DNA, but it's another thing to create a functional chromosome. In fact, in the article you link to, they are discussing a research effort to synthesize a human Y chromosome. As far as I can tell they haven't actually done this yet, they are just proposing to attempt it. George Church is a highly regarded genomicist, but the article is very sloppy about distinguishing what they think they can do from what they've actually done. There has been work with human artificial chromosomes (HAC), but these have been special purpose constructs that successfully replicate and divide in cells, but don't duplicate an entire natural chromosome.

Synthesizing a human genome would just be the start of the therapeutic process. You then face the question of how to place the synthesized genome in the cells of the recipient. Current approaches to gene therapy involve inserting a single "repaired" gene into a virus, and then infecting the relevant tissue with that virus. This doesn't insert the gene into all cells of the body, just the ones infected with the virus. For some simple genetic diseases this is enough to relieve the symptoms of disease. You can't insert an entire human genome into a virus though.

It's also been proposed to harvest stem cells from the recipient, modify them with the repaired gene, and re-insert them in the diseased tissue. Again this would affect only a portion of a single tissue, not all the cells of the body. It's also one thing to insert a short sequence into a stem cell, but nobody knows if you could swap out a stem cell's entire genome and still maintain it as a stem cell. Also, this would only work for tissues that are still actively dividing. Many important tissues (in the brain for example) have stopped dividing or divide only slowly in adults.

Even gene therapy involving single genes has been approved in only a handful of diseases. It's sill almost entirely experimental. What you are suggesting is still in the realm of wild speculation. Speculation can be inspiring and motivates research programs, but don't starting counting chickens yet.


When the cell replicates its DNA, it does so in response to environmental signals that tell the cell it is time to divide. The ideal goal of DNA replication is to produce two identical copies of the double-stranded DNA template and to do it in an amount of time that does not pose an unduly high evolutionarily selective cost. This is a daunting task when you consider that there are

6,500,000,000 base pairs in the human genome and

4,500,000 base pairs in the genome of a typical E. coli strain and that Nature has determined that the cells must replicate within 24 hours and 20 minutes, respectively. In either case, many individual biochemical reactions need to take place.

While ideally replication would happen with perfect fidelity, DNA replication, like all other biochemical processes, is imperfect&mdashbases may

that do not properly base-pair. In many organisms, many of the mistakes that occur during DNA replication

promptly by DNA polymerase itself via a mechanism known as . In , the DNA polymerase "reads" each newly added base via sensing the presence or absence of small structural anomalies before adding the next base to the growing strand. In doing so,

If the polymerase detects that a newly added base has

correctly with the base in the template strand, it adds the next nucleotide. If, however, a wrong nucleotide

to the growing polymer, the misshaped double helix will cause the DNA polymerase to stall, and it will eject the newly made

from the polymerizing site.

DNA strand will enter an exonuclease site. In this site, DNA polymerase can cleave off the last several nucleotides that

to the polymer. Once the polymerase removes the incorrect nucleotides, the DNA strand can return to the polymerizing site and new nucleotides will

again. This proofreading capability comes with some trade-offs: using an error-correcting/more accurate polymerase requires time (the trade-off is speed of replication) and energy (always an important cost to consider). The slower you go, the more accurate you can be. Going too slow, however, may keep you from replicating as fast as your competition, so figuring out the balance is key.

Figure 1. Proofreading by DNA polymerase corrects errors during replication.


Watercress

Shutterstock

Watercress, a delicate leafy green you've likely seen at the supermarket but were too reluctant to throw in the cart, is our top superfood that's better than kale for good reason. In a study published in The American Journal of Clinical Nutrition, researchers observed that participants showed a significant reduction in basal and oxidative DNA damage, as well as a reduced their risk of cancer, after supplementing their diets with just ¾ cup of raw watercress per day. What's more, the beneficial changes were more prevalent in the participants who smoked.


14.6 DNA Repair

By the end of this section, you will be able to do the following:

DNA replication is a highly accurate process, but mistakes can occasionally occur, such as a DNA polymerase inserting a wrong base. Uncorrected mistakes may sometimes lead to serious consequences, such as cancer. Repair mechanisms correct the mistakes. In rare cases, mistakes are not corrected, leading to mutations in other cases, repair enzymes are themselves mutated or defective.

Most of the mistakes during DNA replication are promptly corrected by the proofreading ability of DNA polymerase itself. (Figure 14.17). In proofreading , the DNA pol reads the newly added base before adding the next one, so a correction can be made. The polymerase checks whether the newly added base has paired correctly with the base in the template strand. If it is the right base, the next nucleotide is added. If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the wrong nucleotide. This is performed by the 3' exonuclease action of DNA pol. Once the incorrect nucleotide has been removed, it can be replaced by the correct one.

Some errors are not corrected during replication, but are instead corrected after replication is completed this type of repair is known as mismatch repair (Figure 14.18). Specific repair enzymes recognize the mispaired nucleotide and excise part of the strand that contains it the excised region is then resynthesized. If the mismatch remains uncorrected, it may lead to more permanent damage when the mismatched DNA is replicated. How do mismatch repair enzymes recognize which of the two bases is the incorrect one? In E. coli, after replication, the nitrogenous base adenine acquires a methyl group the parental DNA strand will have methyl groups, whereas the newly synthesized strand lacks them. Thus, DNA polymerase is able to remove the wrongly incorporated bases from the newly synthesized, non-methylated strand. In eukaryotes, the mechanism is not very well understood, but it is believed to involve recognition of unsealed nicks in the new strand, as well as a short-term continuing association of some of the replication proteins with the new daughter strand after replication has completed.

Another type of repair mechanism, nucleotide excision repair , is similar to mismatch repair, except that it is used to remove damaged bases rather than mismatched ones. The repair enzymes replace abnormal bases by making a cut on both the 3' and 5' ends of the damaged base (Figure 14.19). The segment of DNA is removed and replaced with the correctly paired nucleotides by the action of DNA pol. 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.

A well-studied example of mistakes not being corrected is seen in people suffering from xeroderma pigmentosa (Figure 14.20). Affected individuals have skin that is highly sensitive to UV rays from the sun. When individuals are exposed to UV light, pyrimidine dimers, especially those of thymine, are formed people with xeroderma pigmentosa are not able to repair the damage. These are not repaired because of a defect in the nucleotide excision repair enzymes, whereas in normal individuals, the thymine dimers are excised and the defect is corrected. The thymine dimers distort the structure of the DNA double helix, and this may cause problems during DNA replication. People with xeroderma pigmentosa may have a higher risk of contracting skin cancer than those who don't have the condition.

Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations , variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent they are a result of natural reactions taking place within the body.

Mutations may have a wide range of effects. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. These substitutions can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa for example, cytosine, a pyrimidine, is replaced by adenine, a purine. Some point mutations are not expressed these are known as silent mutations. Silent mutations are usually due to a substitution in the third base of a codon, which often represents the same amino acid as the original codon. Other point mutations can result in the replacement of one amino acid by another, which may alter the function of the protein. Point mutations that generate a stop codon can terminate a protein early.

Some mutations can result in an increased number of copies of the same codon. These are called trinucleotide repeat expansions and result in repeated regions of the same amino acid. Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, also known as deletion. If an insertion or deletion results in the alteration of the translational reading frame (a frameshift mutation), the resultant protein is usually nonfunctional. Sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome this is also known as translocation. These mutation types are shown in Figure 14.21.

Visual Connection

A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.

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    Art Connection

    Mutations can lead to changes in the protein sequence encoded by the DNA.

    A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.


    How our cells repair their damaged DNA

    New research shows that some previously overlooked molecules in the body's cells play a key role in the repair of damaged DNA.

    The neglected molecule is called histone 1 (H1), and has so far mainly been described as a molecule that helps to organise DNA within cells. But a new study suggests that H1 also plays an important role in DNA repair.

    The new discovery, according to the scientists behind the new results, could lead us towards a better understanding of how cancer develops in the first place.

    "Cancer is characterised as a disease that causes damage to the DNA. Therefore H1 evidently plays an important role in the defence against cancer, as it&rsquos pivotal in the recruitment of repair proteins that repair this damage,&rdquo says co-author Professor Niels Mailand from The Novo Nordisk Foundation Centre for Protein Research at the University of Copenhagen, Denmark.

    &ldquoThat H1 plays such a central role in such an important mechanism, is completely new knowledge. It also means that other researchers will probably start paying much more attention to H1," he says.

    Colleague: exciting results

    Associate Professor Claus Storgaard Sørensen, a researcher at the Biotech Research & Innovation Centre at the University of Copenhagen, has read the new study and says the results are exciting.

    He was not involved in the research himself, but is thrilled that Mailand and colleagues have discovered the function of H1, which up until this point, had been so difficult to understand.

    Sørensen is especially excited about the discovery of a new mechanism that regulates the repair of DNA, and which plays an important biological role in the immune system.

    "If I had to say what, in my opinion, is the most exciting discovery, then this is it. The researchers have made a major contribution to our understanding of how repair protein 53BP1 is recruited to areas of damaged DNA,&rdquo says Sørensen.

    &ldquoAt the same time, 53BP1 is [shown to be] a very important factor for the immune system. It will be interesting to see if any great discoveries follow in that direction," he says.

    DNA damaged up to 100,000 times per day

    In every cell of the body, DNA suffers damage between 50,000 and 100,000 times a day. This happens when DNA building blocks are swapped or changed around, or where one or both strands of DNA is torn.

    When damage occurs, the cell sends repair proteins to the spot to quickly resolve it. In the process of repairing itself, it may be destroyed or converted to a cancer cell.

    Scientists have known for some time that the protein ubiquitin plays an important role in the recruitment of repair proteins. But until now they didn&rsquot know how ubiquitin actually repaired damaged DNA or how the repair system was regulated.

    The new research discovered that ubiquitin sits within the H1 molecule, close to the damaged DNA. When needed, H1 is nearby to help recruit repair proteins directly to the damaged spot.

    &ldquoIt has been shown previously that the ubiquitin sits on the histones in the vicinity of damaged DNA, but we always believed that it was one of the four core histones that was involved [in repairing damaged DNA],&rdquo says Mailand.

    &ldquoNow it turns out, quite surprisingly, that ubiquitin is first deposited on the extra histone, H1," he says.

    Multiple research spinoffs

    Mailand can see two main spinoffs of the new results.

    First, the new results are an important piece of the puzzle when it comes to understanding the cellular mechanisms that explain how the body repairs damaged DNA and how cancer arises in the first place. Eventually, this could lead to preventative treatments that are targeted at this repair process.

    Second, H1 may have many other undiscovered functions. The recruitment of repair proteins is potentially only one of many.

    "I think there is a lot to explore here. It is like opening a door to a hitherto almost unknown land full of new knowledge,&rdquo says Mailand.


    Biology 171

    By the end of this section, you will be able to do the following:

    DNA replication is a highly accurate process, but mistakes can occasionally occur, such as a DNA polymerase inserting a wrong base. Uncorrected mistakes may sometimes lead to serious consequences, such as cancer. Repair mechanisms correct the mistakes. In rare cases, mistakes are not corrected, leading to mutations in other cases, repair enzymes are themselves mutated or defective.

    Most of the mistakes during DNA replication are promptly corrected by the proofreading ability of DNA polymerase itself. ((Figure)). In proofreading , the DNA pol reads the newly added base before adding the next one, so a correction can be made. The polymerase checks whether the newly added base has paired correctly with the base in the template strand. If it is the right base, the next nucleotide is added. If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the wrong nucleotide. This is performed by the 3′ exonuclease action of DNA pol. Once the incorrect nucleotide has been removed, it can be replaced by the correct one.


    Some errors are not corrected during replication, but are instead corrected after replication is completed this type of repair is known as mismatch repair ((Figure)). Specific repair enzymes recognize the mispaired nucleotide and excise part of the strand that contains it the excised region is then resynthesized. If the mismatch remains uncorrected, it may lead to more permanent damage when the mismatched DNA is replicated. How do mismatch repair enzymes recognize which of the two bases is the incorrect one? In E. coli, after replication, the nitrogenous base adenine acquires a methyl group the parental DNA strand will have methyl groups, whereas the newly synthesized strand lacks them. Thus, DNA polymerase is able to remove the wrongly incorporated bases from the newly synthesized, non-methylated strand. In eukaryotes, the mechanism is not very well understood, but it is believed to involve recognition of unsealed nicks in the new strand, as well as a short-term continuing association of some of the replication proteins with the new daughter strand after replication has completed.


    Another type of repair mechanism, nucleotide excision repair , is similar to mismatch repair, except that it is used to remove damaged bases rather than mismatched ones. The repair enzymes replace abnormal bases by making a cut on both the 3′ and 5′ ends of the damaged base ((Figure)). The segment of DNA is removed and replaced with the correctly paired nucleotides by the action of DNA pol. 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.


    A well-studied example of mistakes not being corrected is seen in people suffering from xeroderma pigmentosa ((Figure)). Affected individuals have skin that is highly sensitive to UV rays from the sun. When individuals are exposed to UV light, pyrimidine dimers, especially those of thymine, are formed people with xeroderma pigmentosa are not able to repair the damage. These are not repaired because of a defect in the nucleotide excision repair enzymes, whereas in normal individuals, the thymine dimers are excised and the defect is corrected. The thymine dimers distort the structure of the DNA double helix, and this may cause problems during DNA replication. People with xeroderma pigmentosa may have a higher risk of contracting skin cancer than those who don’t have the condition.


    Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations , variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent they are a result of natural reactions taking place within the body.

    Mutations may have a wide range of effects. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. These substitutions can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa for example, cytosine, a pyrimidine, is replaced by adenine, a purine. Some point mutations are not expressed these are known as silent mutations. Silent mutations are usually due to a substitution in the third base of a codon, which often represents the same amino acid as the original codon. Other point mutations can result in the replacement of one amino acid by another, which may alter the function of the protein. Point mutations that generate a stop codon can terminate a protein early.

    Some mutations can result in an increased number of copies of the same codon. These are called trinucleotide repeat expansions and result in repeated regions of the same amino acid. Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, also known as deletion. If an insertion or deletion results in the alteration of the translational reading frame (a frameshift mutation), the resultant protein is usually nonfunctional. Sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome this is also known as translocation. These mutation types are shown in (Figure).


    A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.

    Section Summary

    DNA polymerase can make mistakes while adding nucleotides. It edits the DNA by proofreading every newly added base. Incorrect bases are removed and replaced by the correct base before proceeding with elongation. Most mistakes are corrected during replication, although when this does not happen, the mismatch repair mechanism is employed. Mismatch repair enzymes recognize the wrongly incorporated base and excise it from the DNA, replacing it with the correct base. In yet another type of repair, nucleotide excision repair, a damaged base is removed along with a few bases on the 5′ and 3′ end, and these are replaced by copying the template with the help of DNA polymerase. The ends of the newly synthesized fragment are attached to the rest of the DNA using DNA ligase, which creates a phosphodiester bond.

    Most mistakes are corrected, and if they are not, they may result in a mutation, defined as a permanent change in the DNA sequence. Mutations can be of many types, such as substitution, deletion, insertion, and trinucleotide repeat expansions. Mutations in repair genes may lead to serious consequences such as cancer. Mutations can be induced or may occur spontaneously.

    Art Connections

    (Figure) A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    (Figure) If three nucleotides are added, one additional amino acid will be incorporated into the protein chain, but the reading frame wont shift.

    Free Response

    What is the consequence of mutation of a mismatch repair enzyme? How will this affect the function of a gene?

    Mutations are not repaired, as in the case of xeroderma pigmentosa. Gene function may be affected or it may not be expressed.

    An adult with a history of tanning has his genome sequenced. The beginning of a protein-coding region of his DNA reads ATGGGGATATGGCAT. If the protein-coding region of a healthy adult reads ATGGGGATATGAGCAT, identify the site and type of mutation.

    This is a frameshift mutation with a deletion of an “A” in the 12 th position of the coding region.

    Glossary


    71 DNA Repair

    By the end of this section, you will be able to do the following:

    DNA replication is a highly accurate process, but mistakes can occasionally occur, such as a DNA polymerase inserting a wrong base. Uncorrected mistakes may sometimes lead to serious consequences, such as cancer. Repair mechanisms correct the mistakes. In rare cases, mistakes are not corrected, leading to mutations in other cases, repair enzymes are themselves mutated or defective.

    Most of the mistakes during DNA replication are promptly corrected by the proofreading ability of DNA polymerase itself. ((Figure)). In proofreading , the DNA pol reads the newly added base before adding the next one, so a correction can be made. The polymerase checks whether the newly added base has paired correctly with the base in the template strand. If it is the right base, the next nucleotide is added. If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the wrong nucleotide. This is performed by the 3′ exonuclease action of DNA pol. Once the incorrect nucleotide has been removed, it can be replaced by the correct one.


    Some errors are not corrected during replication, but are instead corrected after replication is completed this type of repair is known as mismatch repair ((Figure)). Specific repair enzymes recognize the mispaired nucleotide and excise part of the strand that contains it the excised region is then resynthesized. If the mismatch remains uncorrected, it may lead to more permanent damage when the mismatched DNA is replicated. How do mismatch repair enzymes recognize which of the two bases is the incorrect one? In E. coli, after replication, the nitrogenous base adenine acquires a methyl group the parental DNA strand will have methyl groups, whereas the newly synthesized strand lacks them. Thus, DNA polymerase is able to remove the wrongly incorporated bases from the newly synthesized, non-methylated strand. In eukaryotes, the mechanism is not very well understood, but it is believed to involve recognition of unsealed nicks in the new strand, as well as a short-term continuing association of some of the replication proteins with the new daughter strand after replication has completed.


    Another type of repair mechanism, nucleotide excision repair , is similar to mismatch repair, except that it is used to remove damaged bases rather than mismatched ones. The repair enzymes replace abnormal bases by making a cut on both the 3′ and 5′ ends of the damaged base ((Figure)). The segment of DNA is removed and replaced with the correctly paired nucleotides by the action of DNA pol. 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.


    A well-studied example of mistakes not being corrected is seen in people suffering from xeroderma pigmentosa ((Figure)). Affected individuals have skin that is highly sensitive to UV rays from the sun. When individuals are exposed to UV light, pyrimidine dimers, especially those of thymine, are formed people with xeroderma pigmentosa are not able to repair the damage. These are not repaired because of a defect in the nucleotide excision repair enzymes, whereas in normal individuals, the thymine dimers are excised and the defect is corrected. The thymine dimers distort the structure of the DNA double helix, and this may cause problems during DNA replication. People with xeroderma pigmentosa may have a higher risk of contracting skin cancer than those who don’t have the condition.


    Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations , variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent they are a result of natural reactions taking place within the body.

    Mutations may have a wide range of effects. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. These substitutions can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa for example, cytosine, a pyrimidine, is replaced by adenine, a purine. Some point mutations are not expressed these are known as silent mutations. Silent mutations are usually due to a substitution in the third base of a codon, which often represents the same amino acid as the original codon. Other point mutations can result in the replacement of one amino acid by another, which may alter the function of the protein. Point mutations that generate a stop codon can terminate a protein early.

    Some mutations can result in an increased number of copies of the same codon. These are called trinucleotide repeat expansions and result in repeated regions of the same amino acid. Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, also known as deletion. If an insertion or deletion results in the alteration of the translational reading frame (a frameshift mutation), the resultant protein is usually nonfunctional. Sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome this is also known as translocation. These mutation types are shown in (Figure).


    A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.

    Section Summary

    DNA polymerase can make mistakes while adding nucleotides. It edits the DNA by proofreading every newly added base. Incorrect bases are removed and replaced by the correct base before proceeding with elongation. Most mistakes are corrected during replication, although when this does not happen, the mismatch repair mechanism is employed. Mismatch repair enzymes recognize the wrongly incorporated base and excise it from the DNA, replacing it with the correct base. In yet another type of repair, nucleotide excision repair, a damaged base is removed along with a few bases on the 5′ and 3′ end, and these are replaced by copying the template with the help of DNA polymerase. The ends of the newly synthesized fragment are attached to the rest of the DNA using DNA ligase, which creates a phosphodiester bond.

    Most mistakes are corrected, and if they are not, they may result in a mutation, defined as a permanent change in the DNA sequence. Mutations can be of many types, such as substitution, deletion, insertion, and trinucleotide repeat expansions. Mutations in repair genes may lead to serious consequences such as cancer. Mutations can be induced or may occur spontaneously.

    Visual Connection Questions

    (Figure) A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    (Figure) If three nucleotides are added, one additional amino acid will be incorporated into the protein chain, but the reading frame wont shift.

    Review Questions

    During proofreading, which of the following enzymes reads the DNA?

    The initial mechanism for repairing nucleotide errors in DNA is ________.

    1. mismatch repair
    2. DNA polymerase proofreading
    3. nucleotide excision repair
    4. thymine dimers

    A scientist creates fruit fly larvae with a mutation that eliminates the exonuclease function of DNA pol III. Which prediction about the mutational load in the adult fruit flies is most likely to be correct?

    1. The adults with the DNA pol III mutation will have significantly more mutations than average.
    2. The adults with the DNA pol III mutation will have slightly more mutations than average.
    3. The adults with the DNA pol III mutation will have the same number of mutations as average.
    4. The adults with the DNA pol III mutation will have fewer mutations than average.

    Critical Thinking Questions

    What is the consequence of mutation of a mismatch repair enzyme? How will this affect the function of a gene?

    Mutations are not repaired, as in the case of xeroderma pigmentosa. Gene function may be affected or it may not be expressed.

    An adult with a history of tanning has his genome sequenced. The beginning of a protein-coding region of his DNA reads ATGGGGATATGGCAT. If the protein-coding region of a healthy adult reads ATGGGGATATGAGCAT, identify the site and type of mutation.

    This is a frameshift mutation with a deletion of an “A” in the 12 th position of the coding region.

    Glossary


    Art Connection

    Mutations can lead to changes in the protein sequence encoded by the DNA.

    A frameshift mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.


    Free Response

    What is the consequence of mutation of a mismatch repair enzyme? How will this affect the function of a gene?

    Mutations are not repaired, as in the case of xeroderma pigmentosa. Gene function may be affected or it may not be expressed.

    An adult with a history of tanning has his genome sequenced. The beginning of a protein-coding region of his DNA reads ATGGGGATATGGCAT. If the protein-coding region of a healthy adult reads ATGGGGATATGAGCAT, identify the site and type of mutation.

    This is a frameshift mutation with a deletion of an “A” in the 12 th position of the coding region.


    Watch the video: Spike Protein Goes to Nucleus and Impairs DNA Repair In-Vitro Study (May 2022).