translesion synthesis

Definition

Target type: biologicalprocess

The replication of damaged DNA by synthesis across a lesion in the template strand; a specialized DNA polymerase or replication complex inserts a defined nucleotide across from the lesion which allows DNA synthesis to continue beyond the lesion. This process can be mutagenic depending on the damaged nucleotide and the inserted nucleotide. [GOC:elh, GOC:vw, PMID:10535901]

Translesion synthesis (TLS) is a crucial DNA damage tolerance mechanism that allows cells to bypass DNA lesions that block replicative DNA polymerases. These lesions can arise from various sources, including UV radiation, reactive oxygen species, and chemical mutagens. If left unrepaired, such lesions can lead to replication fork stalling, double-strand breaks, and ultimately cell death.

TLS is carried out by specialized DNA polymerases, known as TLS polymerases, which have relaxed active sites that can accommodate damaged DNA bases. These polymerases are distinct from the replicative polymerases that normally copy DNA during S phase. They are recruited to stalled replication forks by specific factors, such as PCNA (proliferating cell nuclear antigen), which acts as a sliding clamp to enhance polymerase processivity.

The process of TLS can be summarized in the following steps:

1. **Replication fork stalling**: When a replicative polymerase encounters a DNA lesion, it is unable to proceed with DNA synthesis, leading to replication fork stalling.

2. **TLS polymerase recruitment**: Specialized TLS polymerases are recruited to the stalled replication fork.

3. **Bypass synthesis**: The TLS polymerase incorporates nucleotides opposite the damaged base, allowing the replication fork to bypass the lesion. This bypass synthesis is often error-prone, as TLS polymerases lack the same fidelity as replicative polymerases.

4. **Switch back to replicative polymerase**: After bypassing the lesion, the TLS polymerase dissociates from the DNA, and the replicative polymerase resumes synthesis.

TLS plays a critical role in maintaining genome integrity, as it allows cells to tolerate DNA damage and complete DNA replication. However, the error-prone nature of TLS can contribute to mutagenesis and cancer development. Therefore, the balance between TLS-mediated DNA damage tolerance and its potential mutagenic consequences is critical for cellular survival and genomic stability.'
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Proteins (7)

Compounds (29)