Polymerase Delta in Eukaryotes: How is It Transiently Exchanged with Specialized DNA Polymerases During Translesion DNA Synthesis?

Abstract

Precise duplication of the human genome is constantly threatened by a variety of genotoxic insults. During S-phase, those damaged template bases could be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles instead of repairing them, allowing replicative machinery to resume beyond the offending lesions. Two distinct strategies of DDT, template switching and translesion DNA synthesis (TLS), are employed in eukaryotes. In the former process, the newly synthesized sister chromatid is utilized as an undamaged template to restart recombination-dependent DNA synthesis in an error-free manner. While TLS process involves a reversible polymerase switching between replicative and specialized TLS polymerases for the rescue of stalled replication forks, but this process is intrinsically error-prone and thereby increases mutation rates that potentially drive cancer and aging. It still remains controversial on what exact molecular mechanism orchestrates the polymerase switching at blocked primer-template (P/T) junction. In this review, we summarize and discuss the details of multiple types of mechanisms on how DNA polymerase switching is coordinated during TLS in eukaryotic systems. We also propose a hypothesis regarding high-fidelity human DNA polymerase delta (pol δ) and its involvement in polymerase switching based on recent progress in its functional and structural characterization, especially post-translational modification of its subunits, to gain further insights into the intriguing mechanisms of its regulation during TLS.