7.10A: DNA Repair - Biology

7.10A: DNA Repair - Biology

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Most mistakes during replication are corrected by DNA polymerase during replication or by post-replication repair mechanisms.


Explain how errors during replication are repaired

Key Points

  • Mismatch repair enzymes recognize mis-incorporated bases, remove them from DNA, and replace them with the correct bases.
  • In nucleotide excision repair, enzymes remove incorrect bases with a few surrounding bases, which are replaced with the correct bases with the help of a DNA polymerase and the template DNA.
  • When replication mistakes are not corrected, they may result in mutations, which sometimes can have serious consequences.
  • Point mutations, one base substituted for another, can be silent (no effect) or may have effects ranging from mild to severe.
  • Mutations may also involve insertions (addition of a base), deletion (loss of a base), or translocation (movement of a DNA section to a new location on the same or another chromosome ).

Key Terms

  • mismatch repair: a system for recognizing and repairing some forms of DNA damage and erroneous insertion, deletion, or mis-incorporation of bases that can arise during DNA replication and recombination
  • nucleotide excision repair: a DNA repair mechanism that corrects damage done by UV radiation, including thymine dimers and 6,4 photoproducts that cause bulky distortions in the DNA

Errors during Replication

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

Mutations: In this interactive, you can “edit” a DNA strand and cause a mutation. Take a look at the effects!

Most of the mistakes during DNA replication are promptly corrected by DNA polymerase which proofreads the base that has just been added. 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 correct 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 incorrect nucleotide. This is performed by the exonuclease action of DNA pol III. Once the incorrect nucleotide has been removed, a new one will be added again.

Some errors are not corrected during replication, but are instead corrected after replication is completed; this type of repair is known as mismatch repair. The enzymes recognize the incorrectly-added nucleotide and excise it; this is then replaced by the correct base. If this remains uncorrected, it may lead to more permanent damage. 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 incorrectly-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 been completed.

In another type of repair mechanism, nucleotide excision repair, enzymes replace incorrect bases by making a cut on both the 3′ and 5′ ends of the incorrect base. 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.

DNA Damage and Mutations

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. Some mutations are not expressed; these are known as silent mutations. 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 can be of two types: 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. Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, known as a deletion. Sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome.

DNA Repair: Definition and Mechanisms | Genetics

In this article we will discuss about the definition and mechanisms of DNA repair.

Definition of DNA Repair:

One of the main objectives of biological system is to maintain base sequences of DNA from one generation to the other. Changes in DNA sequence arise during replication of DNA damage by chemical mutagens and radiation. During replication if incorrect nucleotides have been added, they are corrected through editing system by DNA Pol I and DNA Pol III.

The other systems also exist for correcting the errors missed by editing function. It is called mismatch repair system. Mismatch repair system edits the errors left by DNA Pol I and DNA III and removes the wrong nucleotides. Proof reading by Pol I and III.

DNA is always damaged and mutated by several chemicals and radiation. Only a few errors accumulate in DNA sequence. The stable errors cause mutation and the rest are eliminated. If errors in DNA sequence are corrected before cell division, no mutation occurs. However, there are some DNA damages which cannot be mutated because the damages are not replicated. Therefore, such damages cause cell death.

There are several types of damages that occur in DNA:

(a) Modification of one or more bases by highly reactive chemicals such as alkylating agents like nitroso-amine and nitrosoguanidine,

(b) Loss of purine bases due to local pH change,

(c) Single strand or double strand break due to bending or shear forces,

(d) Dimer formation (dimerisation) between two adjacent pyrimidine molecules (e.g. T-T) due to ultraviolet and X-ray radiation.

Due to dimerisation no hydrogen bond with opposing purine shall occur. This results in distortion of helix. Most of the spontaneous errors are temporary because they are soon corrected by a process called DNA repair.

Mechanisms of DNA Repair:

There are four major pathways through which thymine-thymine dimer in DNA is repaired: light in­duced repair (photo-reactivation) and light-independent repair (dark re­pair).

(i) Photo-Reactivation:

The UV damages caused in cells are repaired after exposure of cells in visible light. This is called photo-reactivation. In this mechanism an enzyme DNA photolyase cleaves T-T dimer and reverse to monomeric stage (Fig. 9.17). This enzyme is activated only when exposed to visible light.

The mutant cells lack photolyase. This enzyme absorbs energy, binds of cyclobutane ring to defective sites of DNA and promotes cleavage of covalent bonds formed between T-T. This enzyme is found in several bac­teria and placental mammals. Finally, thymine residues are made free and damage is repaired.

Some other photolyases catalyse DNA repair in other ways. The 6-4 photoproduct photolyase repairs the DNA damage i.e. 6-4 photoproduct caused by UV rays. The 6-4 photoproduct is formed due to formation of C4-C6 bond between two adjacent pyrimidines or due to migration of a substituent from C4 position of one pyrimidine to the C6 position of the adjoining pyrimidine. The C4 photoproduct photolyase corrects both the errors.

In Bacillus subtilis a spore photoproduct (5-thyminyl-5, 6-di-hydro-thymine) is produced after UV radiation, but not cyclobutane dimers. In light-independent reaction, photoproduct lyase is formed which repair C-C bond between the two thymines.

(ii) Excision Repair:

It is an enzymatic process. In this mechanism, the damaged portion is removed and replaced by new DNA. The second DNA strand acts as template for the synthesis of new DNA fragment.

Excision repair involves DNA of different lengths such as:

(a) Very short patch repair

The very short patch repair includes the mismatch of a single base, while the latter two deals with mismatches in a long patches of the DNA. The short and long patches of damaged DNA molecules are repaired by uvr genes for example uvr A, B C and D which encode repair endonuclease.

(a) Base excision repair:

The lesions containing non-helix distortion (e.g. alkylating bases) are repaired by base excision repair. It involves at least six enzymes called DNA glycosylases.

Each enzyme recognises at least bases and removes from DNA strand. The enzymes remove deaminated cytosine, deaminated adenine, alkylated or oxidised base. Base excision repair pathway starts with a DNA glycosylation. For example, the enzyme uracyl DNA glycosylase removes the uracyl that has wrongly joined with G which is really deaminated cytosine (Fig. 9.18A).

Then AP- endonuclease (apurinic or apyriminic site) and phosphodiesterase removes sugar-phosphate. AP- sites arise as a result of loss of a purine or a pyrimidine. A gap of single nucleotide develops on DNA which acts as template-primer for DNA polymerase to synthesise DNA and fill the gap by DNA lygase.

(b) Nucleotide excision repair:

Any type of damage having a large change in DNA helix causing helical changes in DNA structure is repaired by this pathway. Such damage may arise due to pyrimidine dimers (T-T, T-C and C-C) caused by sun light and covalently joins large hydrocarbon (e.g. the carcinogen benzopyrene).

In E. coli a repair endonuclease recognises the distortion produced by T-T dimer and makes two cuts in the sugar phosphate backbone on each side of the damage. The enzyme DNA helicases removes oligonucleotide from the double helix containing damage. DNA polymerase III and DNA ligase repair the gap produced in DNA helix (Fig. 9.18B).

(c) Recombination repair (daughter-strand gap repair):

When excision repair mechanisms fails, this mechanism, is required to repair errors. This mechanisms, operates in the viral chromosome in host cell whose DNA is damaged. This mechanism operates only after replication therefore, it is also known as post-replication repair.

Probably RecA protein in E. coli cataly­ses DNA strand for sis­ter-strand exchange. Thus a single stranded DNA segment without any defect is excised from a strand on the ho­mologous DNA segment at the replication fork.

It is inserted into the gap created by excision of thymine dimer (Fig. 9.19). Then the com­bined action of DNA Pol I and DNA ligase joins the inserted piece. The gap formed in donor DNA molecule is also filled by DNA Pol I and ligase enzymes.

(d) Methylation-directed very short patch repair:

Very short patch (VSP) repair is accomplished by involving methylation of bases especially cytosine and adenine. In E. coli methylation of adenine and in a sequence of -GATC- is done by the enzyme methylase (a product of dam gene) on both strands of DNA. After replication only A of -GATC- of one strand remains methylated, while the other remains un-methylated until methylase accomplishes methylation (Fig. 9.20 A-B).

In E. coli repairing activity required four proteins viz., Mutl, MutS, MutU (UvrS) and MutH by the genes mutL, mutS, mutU, and mutH, respectively. The mut genes are the loci which increase the frequency of spontaneous mutation. The un-methylated -GATC allows the MutL to recognise the mismatch during transition period.

This helps MutS to bind to mismatch. MutU supports in unwinding the single strand and single strand DNA binding (SSB) proteins and maintain the structural topography of single strand. MutH cleaves the newly synthesised DNA strand and the protein MutU separates the mismatch strand (A).

However, there is a gradient of methylation along the newly synthesised strand. Least methylation occurs at the replication fork. The parental strand is uniformly methylated.

The methylated bases direct the excision mechanisms to the newly synthesised strand containing the incorrect nucleotides (B). During this transition period, the repair system works and distinguishes the old and new strands and repairs only the new strands.

SOS (Save Our Soul) repair is a by-pass repair system. It is also called emergency repair. The damage in DNA itself induces the, SOS regulatory system which is a complex cellular mechanism.

SOS works where photo-dimers are formed that lead to cell death. SOS is the last attempt to minimise mutation for survival. It induces a number of DNA repair processes. SOS system works in the absence of a DNA template. Therefore, many errors arise leading to mutation.

Generally genes of SOS system remains in repressed condition caused by a protein LexA. Repression of SOS is inactivated by RecA protease. It is formed after the conversion of RecA protein by DNA damage.

DNA damage results in conversion of RecA protein into RecA protease (Fig. 9.21A). RecA protease breaks LexA protein (B). Normally, LexA protein inhibits the activity or recA gene (C) and the DNA repair genes (uvrA and umuD) (D).

Finally, DNA repair genes are activated. SOS system does not repair the large amount of damage. When DNA repair is over, RecA protein loses its proteolytic activity. Then LexA protein accumulates and binds to SOS operator and turns off SOS operator (D). However, repression is not complete. Beside, some RecA protein is also produced that inactivates LexA protein.

31 DNA Repair

DNA replication is a highly accurate process, but mistakes can occasionally occur. If these mistakes are not corrected, this can lead to a mutation: a change in the sequence of DNA. Uncorrected mutations may sometimes lead to serious consequences, such as cancer. One way that a mutation can occur is through DNA polymerase inserting a wrong base. Repair mechanisms typically correct these mistakes, but they occasionally fail to correct the error.

Most of the mistakes during DNA replication are promptly corrected by DNA polymerase (the enzyme that builds new DNA during replication) by proofreading the base that has been just added (Figure 1). In proofreading, the DNA polymerase 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 covalent bond and releases the wrong nucleotide. Once the incorrect nucleotide has been removed, a new one will be added again (Figure 1).

Figure 1 Proofreading by DNA polymerase corrects errors during replication. Photo credit Madeline Price Ball Wikimedia.

Some errors are not corrected during replication, but are instead corrected after replication is completed (Figure 2). The enzymes recognize the incorrectly added nucleotide and excise it this is then replaced by the correct base. If this remains uncorrected, it may lead to more permanent damage.

Figure 2 The incorrectly added base is detected after replication. The 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.

In another type of repair mechanism, enzymes replace incorrect bases by making a cut on both sides of the incorrect base (Figure 3). The segment of DNA is removed and replaced with the correctly paired nucleotides by the action of DNA polymerase. Once the bases are filled in, the remaining gap is sealed by an enzyme called DNA ligase. This repair mechanism is often used when UV exposure causes two thymines to become connected to each other into a thymine-thymine dimer (the small – connecting the two Ts in Figure 3).

Figure 3 Repair of thymine dimers. When exposed to UV, thymines lying adjacent to each other can form thymine dimers. In normal cells, they are excised and replaced.

A well-studied example of mistakes not being corrected is seen in people suffering from xeroderma pigmentosa (Figure 4). Affected individuals have skin that is highly sensitive to UV rays from the sun. When individuals are exposed to UV, thymine-thymine dimers are formed. Normally, these dimers could be are cut out and repaired, but people with xeroderma pigmentosa are not able to repair the damage because of a defect in the repair enzymes. The thymine dimers distort the structure of the DNA double helix, and this causes problems during DNA replication. People with xeroderma pigmentosa have a higher risk of developing skin cancer than those who don’t have the condition.

Figure 4 Xeroderma pigmentosa is a condition in which thymine dimerization from exposure to UV is not repaired. Exposure to sunlight results in skin lesions. (credit: James Halpern et al.)

Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations can also occur because of damage to DNA. Mutations can result from an exposure to a mutagen: chemicals, UV rays, x-rays, or some other environmental agent. Mutations can also 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. Some mutations have no effect on the protein produced by the organism these are known as silent mutations. Other mutations can have serious effects on the organism (such as the mutation that causes xeroderma pigmentosa).

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 gametes. If many mutations accumulate in a cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in a sex cell, the mutation can be passed on to the next generation.

A newly discovered protein repairs DNA

Credit: Pixabay/CC0 Public Domain

Researchers from the University of Seville, in collaboration with colleagues from the Universities of Murcia and Marburg (Germany) have identified a new protein that makes it possible to repair DNA. The protein in question, called cryptochrome, has evolved to acquire this and other functions within the cell.

Ultraviolet radiation can damage the DNA, leading to mutations that disrupt cell function and can allow cancer cells to grow out of control. Our cells have DNA repair systems to defend themselves against this sort of damage. One of these systems is based on a protein, photolyase, which uses blue light to repair DNA damage before it leads to mutations.

Over the course of evolution, the genes for photolyase duplicated and became specialized, creating new proteins, cryptochromes, which have honed their ability to perceive blue light and now perform other functions in cells. For example, cryptochromes use blue light as a signal to regulate plant growth and the rhythm that controls daily activity (the circadian rhythm) in fungi and animals.

The authors of this study discovered that in the fungus Mucor circinelloides, a human pathogen, cryptochromes are the protein responsible for DNA repair after exposure to ultraviolet radiation, a function that should be performed by photolyase. They also suggest that cryptochromes in this fungus acquired their ability to repair DNA during evolution from an ancestral cryptochrome that was not able to repair DNA. This discovery illustrates how proteins change as their functions evolve.

Study reveals structural changes of a key protein involved in DNA repair

Fig. 1: Crystal structure of PARP2 activated by binding to the DNA damage. From: Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition

Researchers of the University of Oulu, Finland, have for the first time uncovered the molecular structure of a key protein, PARP2, when bound to damaged DNA. PARP2 is one of the key enzymes protecting and maintaining our genomes that continuously get damaged by chemicals and radiation from our environment. The new study shows in detail the structure of an activated PARP2 enzyme in complex with oligonucleotides mimicking a damaged DNA.

The new findings were published in Nature Communications.

The study was carried out at Biocenter Oulu and at the Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland, within the Protein and Structural Biology research unit. The research team is led by Professor Lari Lehtiö.

The study reveals for the first time how PARP2 detects a DNA damage and initiates a cascade of events leading to DNA repair. The detection of the DNA damage leads to changes in the structure of the enzyme that explain how PARP2 can bind other molecules when detecting a DNA lesion. This not only clarifies the previously reported results on PARP enzymes but helps studies of DNA repair in future.

The results also provide insights into structure-based development of new anti-cancer drugs which to date have been based on an inactive conformation of the PARP enzymes.

"When solving the structure, we got really excited when we saw the conformational changes this enzyme can undergo during activation—much larger than we previously thought to happen during DNA damage recognition," Professor Lehtiö explains.

Three postdoctoral researchers, Ezeogo Obaji, Mirko Maksimainen and Albert Galera-Prat, together with the team leader solved the structure and validated it by using a range of biochemical and biophysical measurements.

What is DNA repair?

DNA polymerase enzyme sometimes accidentally introduces wrong bases which will disrupt the normal Watson-Crick base paring of the DNA. There are also many possibilities of DNA damage during genetic recombination happens during gametogenesis by meiotic cell division. If the damages or errors in the DNA are not corrected in the somatic cells, it may leads to the development of cancer or it results in the loss of function of genes. More than that, if DNA damages occur in the gametes is not rectified, it will be carried over to next generation through progenies. Thus, damage to the genetic materials is a major threat to all organisms. In order to counteract these threats, cells has evolved many methods to overcome and rectify different types DNA damages. All these methods are collectively termed as DNA REPAIR mechanisms. Similar to DNA replication, transcription and translation, the process of DNA repair is also a prime molecular event in the cells which is very essential for the ultimate survival of the cells and also for the survival of the organism.

DNA Repair and Nobel Prize in Chemistry (2015)

The Royal Swedish Academy of Sciences awarded the 2015 Nobel Prize in Chemistry for the discovery and contributions of DNA repair mechanism. The Nobel Prize in Chemistry this year was shared by three scientists namely Thomas Lindhal, Paul Modrich and Aziz Sancar for their “Mechanistic studies of DNA repair”. The detailed mechanism of DNA repair in the cells that we know today is primarily due to their research. Professor Thomas Lindahl demonstrated that the DNA is an unstable molecule which is subjected to damage even under physiological conditions. He also identified a completely new DNA glycosylase enzyme and described their role DNA repair mechanisms. Professor Paul Modrich transformed the field of mismatch repair to a detailed biochemical understanding first in bacteria and later in eukaryotes. Professor Sancar explained the mechanism of nucleotide excision repair first in bacteria and later in eukaryotic cells. He also explained the molecular mechanisms behind the photoreactivation process, which is type of light dependent DNA repair mechanism. All these contributions helped us to understand the nature of some diseases like cancer and they helped to develop new therapies against many diseases including cancer.

Destructive forces faced by DNA in the cell

There are two categories of destructive forces in the cells that could damage the DNA both structurally and chemically. They are:

(1). Internal or intrinsic factors: they includes:-

Ø Metabolic intermediates

(2). External or extrinsic factors: they includes:-

Ø Radiations (X-rays, UV rays, γ-rays)

Ø Carcinogens/ DNA intercalating agents

As the name suggests, internal factors originate inside the cell itself. Reactive free radicals and metabolic intermediates or metabolic byproducts can severely damage DNA and can induce spontaneous mutations. For example, the oxidative deamination of nucleotides in the cells which results in the conversion of cytosine to uracil is caused by metabolic intermediates. Errors happen during DNA replication and recombination are also considered as the internal factors.

Major external factors that could damage cellular DNA fall under two sub-categories. Among which the different types of radians are most important one. Radiations like UV rays, X-rays and γ-rays can severely disrupt the structure and chemistry of DNA leading to a variety of mutation possibilities. Similarly different carcinogenic chemicals, which we generally called as DNA intercalating agents, can directly react with DNA and can cause different structural and chemical modifications in the DNA.

When the normal conformational chemistry of DNA is lost due to any of these internal or external factors, we can say that there is a lesion in the DNA. As in the image, the normal conformational symmetry of DNA is lost due to formation of thymine dimer by UV Light and this created a bulge in one strand. The bulge produced by thymine dimer can be called as DNA lesion.

The possible structural lesions that can happens to DNA:

(1). Thymine dimer formation:

The most common structural lesion in the DNA is the formation of pyrimidine dimer. It is formed by the covalent bond formation between two adjacent pyrimidine residues such as between two thymine or two cytosine or very rarely a thymine and a cytosine. Pyrimidine dimer formation is caused by the ultraviolet irradiation of DNA. Among the three types of pyrimidine dimers, the thymine dimer formation is the most common one. When DNA is struck with UV light, the hydrogen bonds between the two strands breaks and two covalent bonds are formed between the two thymine residues. The two covalent bonds are formed by the breakage of two double bonds present between C5 and C6 of adjacent thymine residues. The Thymine dimer is also called as cyclobutane photodimer or CPD since it structurally resembles cyclobutane nucleus. If thymine dimer in the DNA is left uncorrected, it will cause melanoma, which is a type of skin cancer.

(2). Spontaneous depurination of DNA

It is due to the spontaneous removal of adenine or guanine residues from the DNA due to the cleavage of N-glycosyl bond which connects the nitrogen base with the deoxyribose sugar. Depurination results in the formation of apurinic site (AP site). Apurinic site structurally disrupt the normal conformation of DNA. If apurinic site is left uncorrected, many types of cancerous growth initiates in the tissue.

(3). Spontaneous deamination of bases in the DNA

As the name suggests, it the removal of amino groups from the nitrogen bases of DNA. Deamination is usually caused by the oxidative removal of amino group from the nitrogen bases. Deamination produces unnatural bases or change in the base sequence and results in point mutation in the DNA. Unnatural bases are bases other than adenine, guanine, thymine, cytosine or urasil. Hypoxanthine and xanthine are the two unnatural bases incorporated to DNA due to spontaneous deamination.

Deamination of adenine creates hypoxanthine formation. Deamination of guanine creates another unnatural base called xanthine. Deamination of cytosine creates uracil. Since, uracil is not a DNA base it will destroy the normal Watson-Crick base pairing of the DNA. Because of the absence of amino group, the deamination of thymine residue is not possible. There is one more type of deamination, in fact it is the most severe and dangerous one. As a part of DNA regulation mechanism, most of the cytosine resides in the DNA will be methylated in its 5th position as 5 methyl cytosine. The deamination of 5-methyl cytosine produces thymine and thus it creates a point mutation.

(4). Errors in DNA replication/Recombination

This is due the accidental inclusion of wrong bases in the DNA by DNA polymerase during DNA replication. DNA polymerase also has an exonuclease activity which usually removes the wrong bases and inserts the correct base by a process called ‘proof reading’. Sometimes the proof reading method fails to detect the wrong base and the wrong base persist in the DNA. If these errors are not corrected, in the next replication cycle base change occurs in the DNA and one daughter DNA get mutated.

Different DNA repair mechanisms in the cell:

In this post, we will just mention the names of different DNA repair mechanisms we have detailed posts with video tutorials for each of these repair mechanisms.

So far there are six different types of DNA repair mechanisms known to science.

(1). Photoreactivation: a light depended DNA repair mechanism which removes thymine dimers

(2). Base Excision Repair (BER): only the damaged base is removed or excised from the DNA strand without removing the normal bases

(3). Nucleotide excision repair (NER): the damaged bases along with a short stretch of healthy stand is removed and refilled with correct bases

(4). Mismatch repair or MMR: As the name suggests it removes the mismatched bases from the DNA and fill with correct bases.

(5). Double strand break repair: double strand break lesions are rectified

(6). Homology directed repair: here a long stretch of DNA repair takes places by consulting with the sequence in the homologous chromosome

There is another type of DNA repair strategy in the cells called SOS response, is actually not a DNA repair mechanism. SOS response is initiated in the cells after a sever DNA damage. SOS responses trigger many molecular processes in the cells and DNA repair is one among these processes.

The repair mechanisms such as, photoreactivation, base excision repair, nucleotide excision repair and mismatch repair, only the damaged strand of the DNA duplex is repaired and the undamaged strand acts as the template strand. However in double strand break repair and homology directed repair, both the strands of a DNA duplex are repaired.

Types of DNA Damage

Based on the source of DNA damage, there are many different types of DNA damages that can occur.

Damages Due to Endogenous Sources

There are mainly five types of DNA damage that are caused by endogenous sources:

Base oxidation (for instance 8-oxo-7 or 8-dihydroguanine, 8-oxo-7), as well as, there could be DNA strand interruptions caused by reactive oxygen species.

Alkylation of bases can happen (mostly methylation) for example formation of 1-methyladenine, 7-methylguanine, 6-O-Methylguanine, etc.

Bulky adduct formation - This occurs due to the covalent bonding of large-sized chemical carcinogens and its main source is heavy cigarette smoking. Few examples of this type are aristolactam I-dA adduct, benzo[a]pyrene diol epoxide-dG adduct, etc.

Hydrolysis of bases - Examples of this are depyrimidination, deamination, and depurination.

Mismatch of bases - This happens because of DNA replication errors where a wrong DNA base gets stitched into a place in a newly forming DNA strand. It could also occur when a DNA base is either skipped or inserted by mistake.

Damages Due to Exogenous Sources

Some examples of DNA damages due to exogenous sources are:

Crosslinking of adjacent thymine and cytokines bases due to UV-B light rays. This results in pyrimidine dimers and is called direct DNA damage.

Free radicals get created by UV-A light. This type of damage is called indirect DNA damage.

Cosmic rays or radioactive decay can cause ionization radiation which can break DNA strands.

An increase in the rate of depurination (this is loss of purine bases from the backbone of DNA) can occur due to thermal disruption at high temperatures. It also causes single-strand breaks.

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What is DNA Repair and its Significance?

The cells within an organism need to have the ability to maintain and conserve their DNA sequence for the survival of the cell and the normal functioning of the organism. DNA repair is how a cell gives a corrective response to DNA damage and alternations. Organisms depend on the genetic information in DNA to survive and reproduce which makes it crucial to maintain the integrity of DNA molecules. In the event that DNA damage can not be repaired, the following major issues might happen:

It affects the function and survival of somatic cells.

Fertility in reproductive cells can get adversely affected.

Can cause gene mutation which could later develop into tumour cells.

DNA damage repair in most cases can restore the structure of DNA but at times it might not be able to eliminate the DNA damage yet allowing the cells to tolerate the damage and survive. The only biological macromolecule that can be repaired in the cell is DNA. Through DNA repair, the genetic stability of species is guaranteed which is very crucial for reducing incidents of defect repair.

Aging neurons prioritize essential genes when repairing DNA

Rather than repairing DNA damage randomly across the genome, neurons appear to focus on mending sections that have genes key to their identity and function, according to a study supported in part by NIA. The findings, which were published in Science, provide a basis for understanding age-related degeneration of the nervous system, and may lead to new strategies for treating diseases such as Alzheimer’s and Parkinson’s. The research was led by scientists at the Salk Institute for Biological Studies, La Jolla, California.

Unlike other cell types, neurons generally cannot be regenerated, so we carry the ones generated in early development throughout our lives. Neurons’ longevity makes it especially important that they continually repair damage to their genome, which holds the genetic instructions they need to function. DNA is damaged through normal cellular wear and tear, and while cells possess the ability to make repairs, that ability does not function as well with increasing age. Research has shown that a decline in DNA maintenance in neurons is linked to a decrease in their function, which may contribute to age-related neurodegenerative diseases.

To learn more about how neurons maintain their DNA, the study’s authors developed a technique they called Repair-seq, which enables them to locate areas in the neuronal genome undergoing repair. Using the new method, they found that neurons concentrate their efforts on specific sections or “hot spots,” rather than fixing errors randomly across the genome. There were roughly 61,000 hot spots, covering about 1.6% of the genome.

When they examined the DNA in the hot spots, they found that it contains a number of genes critical to neurons’ identity and function. They also examined the proteins associated with hot spots and discovered that some showed changes similar to those seen in Alzheimer’s disease. This suggests that impaired DNA repair may contribute to the onset or progression of Alzheimer’s, according to the authors.

By suggesting that neurons respond to age-related deterioration in their DNA repair capacity by prioritizing the maintenance of key genes, the findings provide a new perspective on age-related diseases, and might lead to novel DNA repair-based therapeutic approaches. In addition, Repair-seq offers a powerful new tool for exploring the role of DNA repair in other cell types in various disease states or during the aging process.

This research was supported in part by NIA grants R01-AG056306 and R01-AG056511.

These activities relate to NIH’s AD+ADRD Research Implementation Milestone 2.C, “Create research programs on epigenetics to understand how genetic and environmental factors interact across the lifespan to influence brain aging and risk for disease and to identify potential targets for treatment and prevention.”

DNA repair

DNA repair
The removal of damaged segments, e.g. pyrimidine dimers, from one strand of double-stranded DNA and its correct resynthesis.
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DNA repair theory[edit]
Crossing over and DNA repair are very similar processes, which utilize many of the same protein complexes.[3][5][6] While the formation of chiasma is unique to chromosomal cross over, the use of recombinases and primases to lay a foundation of nucleotides along the DNA sequenece.

DNA Repair
Most of the time, mutation is reversed. DNA repair machines are constantly at work in our cells, fixing mismatched nucleotides and splicing broken DNA strands back together. Yet some DNA changes remain.

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, and then polymerization continues (Figure 9.13 a).

and complementation
As discussed in the earlier part of this article, sexual reproduction is conventionally explained as an adaptation for producing genetic variation through allelic recombination.

genes Genes encoding proteins that can correct errors in DNA sequences.
DNA vector A virus, plasmid, or other vehicle, used to introduce DNA into a cell.
DNP 2,4-dinitrophenol.

: Restoration of the correct nucleotide sequence of a DNA molecule that has acquired a mutation or modification. It includes proofreading by DNA polymerase (see helicase).

ing System
20. One characteristic of DNA molecules is their replication capability. What are the consequences of failures during DNA replication?

and maintenance of chromosome structure. Environmental factors, such asionizing radiation, UV light, and chemicals, can damage DNA. Errors in DNA replication can also lead to mutations.

: Fixing Double-Strand Breaks
Examples of Transcription Regulation in Eukaryotes
Parts of a Chromosome & Their Roles .

diseases are hereditary, because of mutations. There's a difference between DNA damage and mutation. DNA damage is a physical abnormality in the DNA which can be recognized by enzymes. For example single or double strand breaks.

template can be included in the CRISPR/Cas9 system which allows for this DNA sequence to be incorporated at the desired location. The repair template extends beyond the location of the cleaved section of DNA.

processes during cell division. This is because a dividing cell does not recognize the difference between damaged DNA stands and telomeres. Repairing DNA during mitosis could cause telomere fusion, which may result in cell death or chromosome abnormalities.

Genes encoding proteins that correct errors in DNA sequencing. (ORNL)
DNA replication
The use of existing DNA as a template for the synthesis of new DNA strands. In humans and other eukaryotes, replication occurs in the cell nucleus. (ORNL)
DNA sequence .

The causal effects linking genetic alterations and the phenotypic state trajectories of cancer cells are enacted within the TME context and channeled through operational deviations from homeostasis of growth, proliferation, autophagy, angiogenesis, apoptosis, survival, focal adhesion, cell cycle,

Due to the damaging effects that mutations can have on cells, organisms have evolved mechanisms such as

process which occurs after DNA replication.
Post-transcriptional regulation
Regulation of gene expression after the gene has been transcribed into mRNA. For example, by regulation of translation, regulation of protein activity, or regulation of protein turnover.

Due to DNA replication and

mechanisms, mutation rates of individual genes are low, but since each organism has many genes, and a population has many individuals, new mutations arise in populations all the time. Thus, mutations are relatively common, and the mutation rate is an adequate source of new alleles.

The new drug works to restore the activity of hSSB1, preventing the

process from being shut down in the first place.

(TP53) A multifunctional protein Mr 53 kDa regulating cell cycle arrest, apoptosis, senescence,

system. Recognizes and removes mutations that result from base-pairing that is not complementary.
Okazaki fragment - Short stretches of newly synthesized DNA found on the lagging strand during DNA replication.

Errors can occur during DNA replication,

, or DNA recombination.
These can lead to base-pair substitutions, insertions, or deletions, as well as mutations affecting longer stretches of DNA.
These are called spontaneous mutations.

In addition to its AP endonuclease activity, it exhibits other

. In contrast, Nfo (an AP endonuclease) generates 16 and 21mer fragments .
Full article .

A disease (loss of muscle control, and reddening of the skin) in human beings caused by a defect in

mechanisms induced by ionising radiation (X-rays, beta and alpha particles, gamma rays).

DNA ligase - protein that joins (ligates) DNA strands used by cells for

Chimeraplasty A technique of gene therapy dependent on construction of a DNA:RNA oligonucleotide hybrid that once introduced into a cell relies upon

mechanisms to introduce a (corrective) change in the targeted gene.

. Linkage -- the greater association in inheritance of two or more nonallelic genes than is to be expected from independent assortment genes are linked because they reside on the same chromosome.

DNA repair

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DNA repair, any of several mechanisms by which a cell maintains the integrity of its genetic code. 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.

Successful DNA replication requires that the two purine bases, adenine (A) and guanine (G), pair with their pyrimidine counterparts, thymine (T) and cytosine (C). Different types of damage, however, can prevent correct base pairing, among them spontaneous mutations, replication errors, and chemical modification. Spontaneous mutations occur when DNA bases react with their environment, such as when water hydrolyzes a base and changes its structure, causing it to pair with an incorrect base. Replication errors are minimized when the DNA replication machinery “proofreads” its own synthesis, but sometimes mismatched base pairs escape proofreading. Chemical agents modify bases and interfere with DNA replication. Nitrosamines, which are found in products such as beer and pickled foods, can cause DNA alkylation (the addition of an alkyl group). Oxidizing agents and ionizing radiation create free radicals in the cell that oxidize bases, especially guanine. Ultraviolet (UV) rays can result in the production of damaging free radicals and can fuse adjacent pyrimidines, creating pyrimidine dimers that prevent DNA replication. Ionizing radiation and certain drugs, such as the chemotherapeutic agent bleomycin, can also block replication, by creating double-strand breaks in the DNA. (These agents can also create single-strand breaks, though this form of damage often is easier for cells to overcome.) Base analogs and intercalating agents can cause abnormal insertions and deletions in the sequence.

There are three types of repair mechanisms: direct reversal of the damage, excision repair, and postreplication repair. Direct reversal repair is specific to the damage. For example, in a process called photoreactivation, pyrimidine bases fused by UV light are separated by DNA photolyase (a light-driven enzyme). For direct reversal of alkylation events, a DNA methyltransferase or DNA glycosylase detects and removes the alkyl group. Excision repair can be specific or nonspecific. In base excision repair, DNA glycosylases specifically identify and remove the mismatched base. In nucleotide excision repair, the repair machinery recognizes a wide array of distortions in the double helix caused by mismatched bases in this form of repair, the entire distorted region is excised. Postreplication repair occurs downstream of the lesion, because replication is blocked at the actual site of damage. In order for replication to occur, short segments of DNA called Okazaki fragments are synthesized. The gap left at the damaged site is filled in through recombination repair, which uses the sequence from an undamaged sister chromosome to repair the damaged one, or through error-prone repair, which uses the damaged strand as a sequence template. Error-prone repair tends to be inaccurate and subject to mutation.

Often when DNA is damaged, the cell chooses to replicate over the lesion instead of waiting for repair ( translesion synthesis). Although this may lead to mutations, it is preferable to a complete halt in DNA replication, which leads to cell death. On the other hand, the importance of proper DNA repair is highlighted when repair fails. The oxidation of guanine by free radicals leads to G-T transversion, one of the most common mutations in human cancer.

Hereditary nonpolyposis colorectal cancer results from a mutation in the MSH2 and MLH1 proteins, which repair mismatches during replication. Xeroderma pigmentosum (XP) is another condition that results from failed DNA repair. Patients with XP are highly sensitive to light, exhibit premature skin aging, and are prone to malignant skin tumours because the XP proteins, many of which mediate nucleotide excision repair, can no longer function.

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