DNA Polymerase ζ-Dependent Lesion Bypass in Is Accompanied by Error-Prone Copying of Long Stretches of Adjacent DNA

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Genomic instability is associated with multiple genetic diseases. Endogenous and exogenous DNA-damaging factors constitute a major source of genomic instability. Mutations occur when DNA lesions are bypassed by specialized translesion synthesis (TLS) DNA polymerases that are less accurate than the normal replicative polymerases. The discovery of the remarkable infidelity of the TLS enzymes at the turn of the century immediately suggested that their contribution to replication must be tightly restricted to sites of DNA damage to avoid excessive mutagenesis. The actual extent of error-prone synthesis that accompanies TLS in vivo has never been estimated. We describe a novel genetic approach to measure the length of DNA synthesized by TLS polymerases upon their recruitment to sites of DNA damage. We show that stretches of error-prone synthesis associated with the bypass of a single damaged nucleotide span at least 200 and sometimes up to 1,000 nucleotide-long segments, resulting in more than a 300,000-fold increase in mutagenesis in the surrounding region. We speculate that processive synthesis of long DNA stretches by error-prone polymerases could contribute to clustered mutagenesis, a phenomenon that allows for rapid genome changes without significant loss of fitness and plays an important role in tumorigenesis, the immune response and adaptation.

Vyšlo v časopise: DNA Polymerase ζ-Dependent Lesion Bypass in Is Accompanied by Error-Prone Copying of Long Stretches of Adjacent DNA. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005110
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005110

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