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error-prone translesion synthesis

Definition

Target type: biologicalprocess

The conversion of DNA-damage induced single-stranded gaps into large molecular weight DNA after replication by using a specialized DNA polymerase or replication complex to insert a defined nucleotide across the lesion. This process does not remove the replication-blocking lesions and causes an increase in the endogenous mutation level. For example, in E. coli, a low fidelity DNA polymerase, pol V, copies lesions that block replication fork progress. This produces mutations specifically targeted to DNA template damage sites, but it can also produce mutations at undamaged sites. [GOC:elh, GOC:jl, PMID:11485998]

Error-prone translesion synthesis (TLS) is a DNA damage tolerance mechanism that allows cells to replicate their DNA despite the presence of lesions that block the progression of high-fidelity DNA polymerases. This process involves specialized DNA polymerases, known as TLS polymerases, which can bypass the lesions by inserting nucleotides opposite the damaged base. While TLS is essential for survival, it often introduces mutations, making it a major contributor to genomic instability and cancer development.

Here is a detailed description of the biological process:

1. **Damage Encounter:** When a high-fidelity DNA polymerase encounters a DNA lesion, such as a thymine dimer or a bulky adduct, it stalls, unable to proceed with replication.

2. **TLS Polymerase Recruitment:** Specialized TLS polymerases, like Pol η, Pol ι, Pol κ, and Rev1, are recruited to the stalled replication fork. These polymerases have relaxed active sites that can accommodate damaged bases and allow for the insertion of nucleotides opposite the lesion.

3. **Lesion Bypass:** The TLS polymerase binds to the DNA and inserts nucleotides opposite the damaged base. These insertions are often inaccurate, leading to mutations.

4. **Switchback to High-Fidelity Polymerase:** Once the lesion is bypassed, the TLS polymerase dissociates, and a high-fidelity polymerase, such as Pol δ or Pol ε, re-enters the replication fork to continue DNA synthesis.

5. **Consequences of TLS:** Although TLS allows for the completion of DNA replication, the frequent insertion of incorrect nucleotides can lead to mutations. These mutations can have a variety of consequences, including:
- **Increased cancer risk:** Mutations can activate oncogenes or inactivate tumor suppressor genes, increasing the risk of cancer.
- **Genetic disorders:** Mutations can alter gene function, leading to inherited genetic disorders.
- **Drug resistance:** Mutations can alter the activity of drug targets, leading to drug resistance.

6. **Regulation of TLS:** The activity of TLS polymerases is tightly regulated to minimize the risk of mutations. This regulation involves factors like:
- **Ubiquitination:** The ubiquitination of PCNA (proliferating cell nuclear antigen) recruits TLS polymerases to the replication fork.
- **DNA damage response:** The DNA damage response pathway activates downstream signaling cascades that regulate TLS polymerase activity.
- **Cell cycle control:** TLS is primarily active during the S phase of the cell cycle, when DNA replication occurs.

In summary, TLS is a complex and tightly regulated process that allows cells to tolerate DNA damage. However, it is a double-edged sword, as it can introduce mutations that contribute to genomic instability and disease.'
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Proteins (4)

ProteinDefinitionTaxonomy
DNA polymerase iotaA DNA polymerase iota that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UNA4]Homo sapiens (human)
DNA polymerase etaA DNA polymerase eta that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y253]Homo sapiens (human)
DNA polymerase iotaA DNA polymerase iota that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UNA4]Homo sapiens (human)
DNA polymerase kappaA DNA polymerase kappa that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UBT6]Homo sapiens (human)

Compounds (8)

CompoundDefinitionClassesRoles
aurintricarboxylic acidaurintricarboxylic acid : A member of the class of quinomethanes that is 3-methylidene-6-oxocyclohexa-1,4-diene-1-carboxylic acid in which the methylidene hydrogens are replaced by 4-carboxy-3-hydroxyphenyl groups. The trisodium salt is the biological stain 'chrome violet CG' while the triammonium salt is 'aluminon'.

Aurintricarboxylic Acid: A dye which inhibits protein biosynthesis at the initial stages. The ammonium salt (aluminon) is a reagent for the colorimetric estimation of aluminum in water, foods, and tissues.
monohydroxybenzoic acid;
quinomethanes;
tricarboxylic acid
fluorochrome;
histological dye;
insulin-like growth factor receptor 1 antagonist
candesartan cilexetilcandesartan cilexetil: a prodrug which is metabolized to an active form candesartan to exert its biological effectsbiphenyls
ellagic acidcatechols;
cyclic ketone;
lactone;
organic heterotetracyclic compound;
polyphenol
antioxidant;
EC 1.14.18.1 (tyrosinase) inhibitor;
EC 2.3.1.5 (arylamine N-acetyltransferase) inhibitor;
EC 2.4.1.1 (glycogen phosphorylase) inhibitor;
EC 2.5.1.18 (glutathione transferase) inhibitor;
EC 2.7.1.127 (inositol-trisphosphate 3-kinase) inhibitor;
EC 2.7.1.151 (inositol-polyphosphate multikinase) inhibitor;
EC 2.7.4.6 (nucleoside-diphosphate kinase) inhibitor;
EC 2.7.7.7 (DNA-directed DNA polymerase) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
food additive;
fungal metabolite;
geroprotector;
plant metabolite;
skin lightening agent
pecilocinpecilocin: fungicidal antibiotic produced by Paecilomyces varioti Bainier var. antibioticus; structureN-acylpyrrolidine
manoalidemanoalide : A sesterterpenoid isolated from the marine sponge Luffariella variabilis and which has been shown to exhibit inhibitory activity towards phospholipase A2.

manoalide: phospholipase A2 inhibitor; sesterterpene from marine sponge L. variabilis; structure given in first source
butenolide;
lactol;
sesterterpenoid
EC 3.1.1.4 (phospholipase A2) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
metabolite
3-o-methylfunicone3-O-methylfunicone: derived from Penicillium pinophilum; structure in first source
sch 725680Sch 725680: an aazaphilone from Aspergillus sp.; structure in first source
pinophilin bpinophilin B: from cultures of a fungus (Penicillium pinophilum Hedgcok) derived from a seaweed; structure in first source