DNA Damage Tolerance
Synonyms
Definition
DNA damage tolerance is a biological mechanism in response to DNA damage which overcomes arrested DNA replication as a result of unrepaired DNA damage, leading to elimination of its potential lethal effects.
Characteristics
Schematic summary of consequences of DNA damage in mammalian cells. Note that DNA damage tolerance mechanism promotes cell survival, and defects in error-free translesion DNA synthesis result in predisposition to cancer
Mechanism
Nonreplicative DNA Polymerases
A number of DNA polymerases have been identified specifically responsible for overcoming damage-induced replication arrest in human cells, which are also called specialized DNA polymerase (or bypass polymerase). So far ten of those polymerases have been identified in humans including Rev1, Polyη, κ, ι, λ, μ, β, θ, υ, and ζ. Unlike replicative DNA polymerases, which can only use the opposite strand as template to initiate DNA synthesis, the specialized polymerases are able to promote stable incorporation of nucleotides opposite the lesion when replication is blocked by a damage. In addition to the conventional domains commonly found in all DNA polymerases such as “fingers,” “thumbs,” and “palm” domains, many of the specialized DNA polymerases have a “little finger” domain and catalytic sites which provide a flexible active site and allow the replicative bypass of various types of template structure. During an arrested replication, these polymerases take over temporarily from the replicative DNA polymerases and use either the damaged DNA strand or the newly synthesized DNA strand as a template to proceed with replication. This event is referred as “polymerase switching.” This step is essential for the specialized polymerases to transiently occupy the primer template for initiating synthesis to bypass the damaged site. Unlike the high-fidelity replicative DNA polymerases, these specialized polymerases have low fidelity of DNA synthesis and are responsible for mutagenesis in the genome. It is speculated that the reason that these polymerases are excluded from normal DNA replication is to maintain genomic stability in normal cells.
Translesion DNA Synthesis
The predominant and most well-studied DNA tolerance mechanism is known as translesion synthesis (TLS). This process allows tolerance of DNA damage by employing specialized DNA polymerases to synthesize DNA directly in order to bypass template DNA damage. The outcome of this process can be both error-free and error-prone. When normal DNA synthesis is blocked by a lesion on one of the template strands, the specialized DNA polymerase(s) use the newly synthesized daughter strand as template to proceed DNA synthesis. Therefore, copying of the damaged site of DNA template is avoided and the DNA replication continues. Because the newly synthesized daughter strand, instead of the damaged strand, is used as template, this process is also named “template switching.” In this process, the correct nucleotide is incorporated opposite the damage site; therefore, it is error-free. In contrast, when specialized polymerase(s) use the damaged template to proceed with DNA synthesis, errors may occur. This process is called lesion bypass and usually error-prone because of lack of correct template. However, if the correct nucleotide is incorporated opposite to the damage site, it can be error-free. When an incorrect nucleotide is incorporated opposite the damage site and subsequently extended, a base mutation occurs. Therefore, the error-free lesion bypass is a mutation-avoiding mechanism, and error-prone lesion bypass is a mutation-generating mechanism. In humans, the poly η is demonstrated to be one of the error-free specialized polymerases, while Pol ι, κ, ζ, and Rev1 are found to be mutagenic specialized polymerases. The error-prone translesion synthesis contributes a major mechanism of DNA damage-induced mutagenesis in humans.
Association with Cancer
Although the majority of polymerase errors are corrected by mismatch repair mechanism, the repair system may not function with 100% efficiency; therefore, errors are likely to escape correction and extended during subsequent replication. In addition, some unrepaired DNA damage, spontaneously formed or induced by environmental agents, will be processed by an error-prone lesion bypass mechanism leading to mutagenesis. Therefore, mutations are generated every time the cell replicates itself. Accumulation of mutations in DNA results in activation of proto-oncogenes and inactivation of tumor suppressor genes resulting in malignant transformation. The significance of translesion synthesis in the development of human cancer comes from the identification of germ line mutations of the Poly η gene in the form of a hereditary disease named xeroderma pigmentosum variant (XPV). Poly η is a highly specific bypass polymerase in repairing UV-induced thymidine dimers in an error-free manner. Loss of its function leads to increased UV-induced mutagenesis and hypersensitivity to sunlight. These XPV patients are hypermutable by UV radiation and develop cancer on sun-exposed skin at a very young age. Skin abnormalities are caused by defects in bypassing UV-induced DNA damage leading to cell death or malignancy.
References
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