Roadblocks and detours during DNA replication: mechanisms of mutagenesis in mammalian cells.

Mutations in specific genes result in birth defects, cancer, inherited diseases or lethality. The frequency with which DNA damage is converted to mutations increases dramatically when the cellular genome is replicated. Although DNA damage poses special problems to the fidelity of DNA replication, efficient mechanisms exist in mammalian cells which function to replicate their genome despite the presence of many damaged sites. These mechanisms operate in either error-prone or error-free modes of DNA synthesis, and frequently involve DNA strand-pairing reactions. Genetic studies in yeast and other eukaryotes suggest that replication through DNA damage is highly regulated and catalysed by complex biochemical machineries composed of many specialized gene products. Knowledge of the molecular details by which such factors facilitate the replication of damaged DNA in mammalian cells should reveal basic rules about how DNA damage induces mutagenesis and carcinogenesis.