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What would happen if there were an error in the DNA complementary base pairing? explain.

What would happen if there were an error in the DNA complementary base pairing? explain.

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Expert Solution

Complementary base pairing is the phenomenon where in DNA guanine always hydrogen bonds to cytosine and adenine always binds to thymine. The bond between guanine and cytosine shares three hydrogen bonds compared to the A-T bond which always shares two hydrogen bonds.

Replication errors and DNA damage are actually happening in the cells of our bodies all the time. In most cases, however, they don’t cause cancer, or even mutations. That’s because they are usually detected and fixed by DNA proofreading and repair mechanisms. Or, if the damage cannot be fixed, the cell will undergo programmed cell death (apoptosis) to avoid passing on the faulty DNA.

Mechanisms used by cells to correct replication errors and fix DNA damage, including:

During DNA synthesis, most DNA polymerases "check their work," fixing the majority of mispaired bases in a process called proofreading.

Immediately after DNA synthesis, any remaining mispaired bases can be detected and replaced in a process called mismatch repair.

If DNA gets damaged, it can be repaired by various mechanisms, including chemical reversal and excision repair.

1. Proofreading: DNA polymerases are the enzymes that build DNA in cells. During DNA replication (copying), most DNA polymerases can “check their work” with each base that they add. This process is called proofreading. If the polymerase detects that a wrong (incorrectly paired) nucleotide has been added, it will remove and replace the nucleotide right away, before continuing with DNA synthesis.

2. Mismatch repair: Recognizes mismatched that are incorporated during DNA replication.Many such mismatched bases are removed by the proofreading activity of DNA polymerase.Any missed repair are subjected to a later correction by the mismatch repair system, which scans the newly replicated DNA.If a mismatch is found, the enzymes of this repair system are able to identify and excise the mismatched base specifically from the newly replicated DNA strand, allowing the error to be corrected and the original sequence restored.

Mismatch repair in E. coli

In E. Coli, the ability of the mismatch repair system to distinguish b/w parental DNA and newly synthesized DNA is based on the fact that DNA of this bacterium is modified by the methylation of adenine residues within the sequence GATC to form 6-methyladenine.Newly synthesized DNA are not methylated and can be specifically recognized by mismatch repair enzymes.Mismatch repair is initiated by MutS, which recognizes the mismatch and forms a complex with two othre proteins called MutL and MutH.The MutH endonuclease then cleaves the unmethylated DNA strand at a GATC sequence. MutL and MutS then act together with an exonuclease and a helicase to excise the DNA b/w the strand break and the mismatch.The resulting gap being filled by DNA polymerase and ligase.

Eukaryotic mismatch repair

Eukaryotes have a similar mismatch repair system. But the mechanism with which they identify newly replicated DNA differs from that used by E.Coli. Eukaryotes do not have a homolog of MutH and no DNA methylation.Instead, SS breaks in the newly synthesized strand specifies the strand to be seperated.Eukaryotic homologs of MutS and MutL bind to the mismatched base, as in E.Coli and direct excision of the DNA b/w a strand break and mismatch.The newly synthesized lagging strand can be identified by nicks at either end of the okazaki fragments, whereas the leading strand might be identified by its growing 3’ end.

3. Reversal of DNA damage: Most damage to DNA is repaired by removal of the damaged bases followed by re-synthesis of the excised region.Some lesions in DNA, however , can be repaired by direct reversal of the damage- a more efficient way of dealing with specific types of DNA damage that occur frequently.Only a few types of DNA damage are repaired in this manner.Particularly pyrimidine dimers, resulting from exposure to UV light.Alkylated guanine residues, modified by the addition of methyl/ethyl group at the O6 position of the purine ring.One mechanism of repairing UV-induced pyrimidine dimers is direct reversal of dimerization reaction, known as photoreactivation.The process is so called because energy derived from from visible light is utilized to break the cyclobutane ring structure.

Another form of direct repair deals with damage resulting from the reaction between alkylating agents and DNA.Alkylating agents are reactive compounds that can transfer methyl/ethyl groups to a DNA base, thereby chemically modifying the base.A particular important type of damage is methylation of the O6 position of guanine.
O6 methyl guanine forms complementary base pairing with thymine instead of cytosine.This lesion can be repaired by an enzyme O6 methylguanine methyltransferase.

4. Excision repair: Damage to one or a few bases of DNA is often fixed by removal (excision) and replacement of the damaged region. In base excision repair,just the damaged base is removed. In nucleotide excision repair, as in the mismatch repair we saw above, a patch of nucleotides is removed.

Base excision repair

Base excision repair is a mechanism used to detect and remove certain types of damaged bases. A group of enzymes called glycosylases play a key role in base excision repair. Each glycosylase detects and removes a specific kind of damaged base.

For example, a chemical reaction called deamination can convert a cytosine base into uracil, a base typically found only in RNA. During DNA replication, uracil will pair with adenine rather than guanine (as it would if the base was still cytosine), so an uncorrected cytosine-to-uracil change can lead to a mutation.

To prevent such mutations, a glycosylase from the base excision repair pathway detects and removes deaminated cytosines. Once the base has been removed, the "empty" piece of DNA backbone is also removed, and the gap is filled and sealed by other enzymes.

Nucleotide excision repair:

DNA glycosylase recognize only specific forms of damaged bases.
Other excision repair systems recognize a wide variety of damaged bases that distort the DNA molecule.This widespread form of DNA repair is known as nucleotide-excision repair, because the damaged bases (eg: a thymine dimer) are removed as part of an oligonucleotide containing the lesion.

IN E.Coli, NER is catalyzed by the products of three genes (uvrA, uvrB and uvr C). Mutations at these loci result in extreme sensitivity to UV light.The protein Uvr A recognizes damaged DNA and recruits UvrB and UvrC to the site of lesion.Uvr B and Uvr C then cleaves on the 3’ and 5’ sides of the damaged site, respectively.Thus excising an oligonucleotide consisting of 12 or 13 bases.The UvrABC complex is frequently called an exinuclease.The term indicates its ability to excise an oligonucleotide.Action of helicase is then required to remove the damage containing oligonucleotide from the double-stranded DNA molecule, and the resulting gap is filled by DNA polymerase and sealed by ligase.

Nucleotide Excision repair in mammalian cells.
1. The initial step in excision repair in mammalian cells involves recognition of disrupted base pairing by XPC.
2.This is followed by cooperative binding of XPA and RPA (replication protein A), a ss binding protein., and a multisubunit trnascription factor TFIIH, required to initiate transcription in eukaryotes.In some cases XPE may also play a role in damage recognition.

Two subunits of TFIIH are XPB and XPD proteins , which act as helicases to unwind approx 25bp of DNA around the site of damage.
The The XPG protein is then recruited to the complex followed by recruitment of XPF as a heterodimer with ERCC1( a repair protein ).
XPF/ERCC1 and XPG are endonucleases, which cleave DNA on the 5’ and 3’ sides of the damaged sites, respectively.This cleavage excises an oligonucleotide consisting of approx 30 bases.The resulting gap is then filled by DNA polymerase delta (in association with RFC and PCNA) AND sealed by ligase.


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