translesionsynteesissä

Translesion synthesis (TLS) is a specialized DNA damage tolerance mechanism that allows cells to replicate across DNA lesions. Unlike standard DNA polymerases that stall when encountering damaged DNA, TLS polymerases are able to insert nucleotides opposite to these lesions, thereby bypassing the damage and allowing replication to proceed. This process is crucial for cell survival, as unrepaired DNA damage can lead to replication fork collapse and cell death.

TLS polymerases are characterized by their low fidelity and ability to accommodate a wide range of damaged bases in their active sites. They often have a wider active site pocket compared to replicative polymerases, which facilitates the binding and incorporation of modified nucleotides. While TLS can prevent catastrophic replication blockage, it comes at the cost of introducing mutations. This is because TLS polymerases may insert incorrect nucleotides opposite the lesion or even bypass the lesion entirely.

The cellular machinery for TLS involves a network of proteins, including the TLS polymerases themselves, as well as proteins that recognize and recruit these polymerases to the replication fork. Damage checkpoints also play a role in regulating TLS, ensuring that it is activated only when necessary and that its mutagenic potential is controlled. In humans, defects in TLS pathways have been linked to various diseases, including cancer and developmental disorders, highlighting its importance in maintaining genomic integrity.