Translesion DNA synthesis

Last updated on: 03.07.2024

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History
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The studies of Evelyn Witkin, working with bacteria that could be killed but not mutated by UV irradiation, introduced the concept of damage-inducible, error-prone translesion DNA synthesis. These ideas were further developed in 1970 by Miroslav Radman in a privately circulated letter, in which he proposed that "SOS replication" was the result of the induction of an error-prone DNA polymerase under the control of the recA and lexA genes. This idea later developed into the "SOS repair hypothesis".

Interestingly, damage-induced mutagenesis (see induced mutation below) was not only dependent on chromosomally encoded bacterial genes, but could also be dramatically increased if the host bacterium harbored certain self-transmissible R plasmids, such as ColIb or R-Utrecht (R205).

In the early 1970s, Donald MacPhee even demonstrated that R-Utrecht codes for an error-prone DNA polymerase. The ability of R plasmids to increase cellular mutagenesis prompted Ames and colleagues to introduce pKM101 into Salmonella strains they had developed to detect carcinogens in order to increase the sensitivity of their tests. Further support for the notion of so-called "mutagenesis proteins" was provided shortly thereafter when Kato and Shinoura isolated umu/uvm strains of E. coli that were specifically defective for damage-induced mutagenesis. Interestingly, DNA sequence analysis of the mutagenesis-promoting genes of pKM101 (called mucAB) revealed that they are closely related to the umuDC genes of E. coli. Many of these R plasmids have now been fully sequenced and have been shown to harbor orthologs of the E. coli umuDC genes, similar to pKM101.

Definition
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Translesion DNA synthesis is a term used in genetics. Translesion DNA synthesis, or TLS for short, is a genetic mechanism that enables the cell to replicate damaged DNA when conventional DNA replication mechanisms are blocked due to damage to the DNA. To ensure this, specialized DNA polymerases take the place of normal DNA polymerases in translesion DNA synthesis, which are able to continue replication despite the defective DNA sequence.

Classification
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The human cell has five translesion DNA polymerases (Pol I - V) that can synthesize across damaged sites. Some of them are specific for one type of damage and can incorporate the correct nucleotide on the new strand. However, if the original sequence cannot be identified, a random nucleotide is incorporated. It is now known that TLS is largely facilitated by specialized DNA polymerases that can accommodate bulky adducts in their active sites. Pol V can traverse a wide range of DNA lesions and performs the majority of mutagenic TLS, while Pol II and Pol IV appear to be more specialized TLS polymerases.

General information
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These specialized DNA polymerases can copy over damaged base pairs, which usually leads to mutations. Although translesion DNA synthesis helps to maintain DNA replication, it also carries the risk of genetic alterations that can lead to diseases such as cancer. Therefore, the regulation of this process is of great importance for cell health.

Note(s)
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All living organisms are constantly exposed to agents that damage their DNA and thus jeopardize the integrity of their genome. As a result, cells are equipped with a variety of DNA repair enzymes to remove the damaged DNA. Nevertheless, situations arise in which lesions persist that block the progression of the cell's replicase. In such situations, the cells are forced to choose between recombination-mediated "damage avoidance" pathways or the use of a specialized DNA polymerase (Pol I-V) to overcome the blocking lesion. The latter process is referred to as translesion DNA synthesis (TLS).

Literature
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  1. Shilkin ES et al. (2020) Translesion DNA Synthesis and Carcinogenesis. Biochemistry (Mosc) 85:425-435.
  2. Vaisman A et al. (2012) Translesion DNA Synthesis. EcoSal Plus 5:10.1128/ecosalplus.7.2.2.

Incoming links (2)

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Last updated on: 03.07.2024