Post-replicative lesion processing limits DNA damage-induced mutagenesis.

Area of Science:

• Molecular Biology
• Genetics
• DNA Repair Mechanisms

Background:

• DNA lesions pose a significant threat to genome stability.
• Cells employ Translesion Synthesis (TLS) and damage avoidance (DA) pathways to navigate DNA replication challenges posed by lesions.
• TLS involves nucleotide insertion opposite lesions, risking mutations, while DA uses homologous recombination for error-free bypass.

Purpose of the Study:

• To investigate the temporal dynamics of DNA lesion bypass mechanisms in yeast.
• To understand how the timing of lesion bypass influences the accuracy of DNA replication.
• To elucidate the interplay between TLS and DA pathways in maintaining genome integrity.

Main Methods:

• Investigated lesion bypass timing in yeast models.
• Analyzed the roles of specific DNA polymerases (η, Rev1, Pol ζ) and Exo1 nuclease.
• Examined the competition between TLS and DA pathways at post-replicative gaps.

Main Results:

• DNA polymerase η bypasses UV-induced cyclobutane pyrimidine dimers at the replication fork immediately after lesion encounter.
• TLS of (6-4) photoproducts and G-AAF adducts occurs in post-replicative gaps, behind the fork, mediated by Rev1 and Pol ζ.
• TLS competes with the error-free DA pathway in post-replicative gaps, reducing overall mutagenicity.
• Exo1 nuclease modulates post-replicative gap size, influencing the balance between TLS and DA.

Conclusions:

• The timing of TLS is crucial for accurate DNA lesion bypass, with different lesions and polymerases exhibiting distinct bypass strategies.
• Competition between TLS and DA pathways in post-replicative gaps is a key mechanism for minimizing replication errors.
• Exo1 nuclease plays a regulatory role in DNA damage tolerance by controlling the balance between mutagenic and error-free bypass.