error-free 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 but does not causes an increase in the endogenous mutation level. For S. cerevisiae, RAD30 encodes DNA polymerase eta, which incorporates two adenines. When incorporated across a thymine-thymine dimer, it does not increase the endogenous mutation level. [GOC:elh]

Error-free translesion synthesis (TLS) is a crucial DNA repair mechanism that allows cells to bypass damaged DNA bases while maintaining the integrity of the genetic code. This process involves specialized DNA polymerases that can replicate past lesions that would normally stall the replicative polymerases.

Here's a detailed breakdown of the biological process:

1. **DNA Damage Recognition:** When DNA polymerase encounters a damaged base (e.g., a thymine dimer caused by UV radiation), it stalls, unable to proceed. This triggers the recruitment of specialized translesion synthesis (TLS) polymerases to the site of damage.

2. **TLS Polymerase Recruitment:** TLS polymerases are distinct from the replicative polymerases (Pol α, δ, and ε) and have unique structural features that allow them to accommodate damaged DNA. Proteins like PCNA (proliferating cell nuclear antigen) act as a sliding clamp, facilitating the switch from replicative to TLS polymerases.

3. **Bypass Synthesis:** Once bound to the damaged DNA, TLS polymerases utilize a different active site geometry and base pairing rules to synthesize DNA past the lesion. Some TLS polymerases can insert the correct base opposite the damaged base, while others may insert a non-canonical base that can be later replaced by a correct base.

4. **Switch Back to Replicative Polymerase:** After the TLS polymerase has bypassed the lesion, the replicative polymerase can resume DNA synthesis. This switching mechanism ensures that the majority of the genome is replicated by the high-fidelity replicative polymerases, minimizing the risk of mutations.

5. **Error-Free Repair:** Error-free translesion synthesis relies on the insertion of the correct base opposite the lesion. This accuracy is achieved by various mechanisms, including:
- **Specialized Active Sites:** TLS polymerases have evolved active sites that can accommodate damaged bases, allowing for accurate base pairing.
- **Base Excision Repair (BER):** After TLS, the damaged base can be removed by BER, allowing the correct base to be inserted.
- **Mismatch Repair (MMR):** MMR can also correct mismatches introduced during TLS, ensuring that the DNA sequence is restored to its original state.

6. **Importance of Error-Free TLS:** While TLS is essential for surviving DNA damage, it is a relatively error-prone process. Error-free TLS minimizes the risk of mutations and genomic instability, protecting cells from cancer and other genetic diseases.

7. **Regulation of TLS:** The activity of TLS polymerases is tightly regulated to minimize the risk of mutations. Several cellular factors, including the availability of TLS polymerases, the type of DNA damage, and the cellular stress response, influence TLS activity.

Error-free translesion synthesis is a complex and tightly regulated process that is essential for maintaining genome integrity. By allowing cells to bypass damaged DNA bases while minimizing the introduction of mutations, TLS plays a critical role in protecting cells from the deleterious effects of DNA damage.'
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Proteins (3)

Compounds (12)