Error-Prone Repair and Translesion Synthesis

KEY CONCEPTS
- Damaged DNA that has not been repaired causes prokaryotic DNA polymerase III to stall during replication.
- DNA polymerase V (encoded by umuCD) or DNA polymerase IV (encoded by dinB) can synthesize a complement to the damaged strand.
- The DNA synthesized by repair DNA polymerases often has errors in its sequence.
The existence of repair systems that engage in DNA synthesis raises the question of whether their quality control is comparable with that of DNA replication. As far as we know, most systems, including uvr-controlled excision repair, do not differ significantly from DNA replication in the frequency of mistakes. Error-prone synthesis of DNA, however, occurs in E. coli under certain circumstances.
The error-prone pathway, also known as translesion synthesis, was first observed when it was found that the repair of damaged λ phage DNA is accompanied by the induction of mutations if the phage is introduced into cells that had previously been irradiatedwith  UV light. This suggests that the UV irradiation of the host has activated functions that generate mutations when repairing λ DNA.
The mutagenic response also operates on the bacterial host DNA. What is the actual error-prone activity? It is a specialized DNA polymerase that inserts random (and thus usually incorrect) bases when it passes any site at which it cannot insert complementary base pairs in the daughter strand. Mutations in the genes umuD and umuC abolish UV-induced mutagenesis. This implies that the UmuC and UmuD proteins cause mutations to occur after UV irradiation. The genes constitute the umuDC operon, whose expression is induced by DNA damage. Their products form a complex, UmuD′₂C, which consists of two subunits of a truncated UmuD protein (UmuD′) and one subunit of UmuC. UmuD is cleaved by RecA, which is activated by DNA damage.
The UmuD′₂C complex has DNA polymerase activity. It is called DNA polymerase V and is responsible for synthesizing new DNA to replace sequences that have been damaged by UV irradiation. This is the only enzyme in E. coli that can bypass the classic pyrimidine dimers produced by UV irradiation (or other bulky adducts). The polymerase activity is error prone. Mutations in either umuC or umuD inactivate the enzyme, which makes high doses of UV irradiation lethal.
How does an alternative DNA polymerase get access to the DNA? When the replicase (DNA polymerase III) encounters a block, such as a thymidine dimer, it stalls. It is then displaced from the replication fork and replaced by DNA polymerase V. In fact, DNA polymerase V uses some of the same ancillary proteins as DNA polymerase III. The same situation is true for DNA polymerase IV, the product of dinB, which is another enzyme that acts on damaged DNA.
DNA polymerases IV and V are part of a larger family of translesion polymerases, which includes eukaryotic DNA polymerases and whose members are specialized for repairing damaged DNA. In addition to the dinB and umuCD genes that code for DNA polymerases IV and V in E. coli, this family also includes the RAD30 gene coding for DNA polymerase η of Saccharomyces cerevisiae and the XPV gene described previously that encodes the human homolog. A difference between the bacterial and eukaryotic enzymes is that the latter are not error prone at thymine dimers: They accurately introduce an A-A pair opposite a T-T dimer. When they replicate through other sites of damage, however, they are more prone to introduce errors.

مواضيع ذات صلة

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MicroRNAs Are Widespread Regulators in Eukaryotes

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Introduction to Noncoding RNA

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DNA Methylation Is Responsible for Imprinting

Chromosome Condensation Is Caused by Condensins