Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress

Abstract

DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, conversely, excessive instability appears to suppress tumorigenesis and is associated with improved prognosis. These findings support the view that karyotypic diversity, necessary to adapt to selective pressures, may be limited in tumors so as to reduce the risk of excessive instability. This review aims to highlight the contribution of specialized DNA polymerases in limiting extreme genetic instability by allowing DNA replication to occur even in the presence of DNA damage, to either avoid broken forks or favor their repair after collapse. These mechanisms and their key regulators Rad18 and Polθ not only offer diversity and evolutionary advantage by increasing mutagenic events, but also provide cancer cells with a way to escape anti-cancer therapies that target replication forks.

Beyond the Lesion: Back to High Fidelity DNA Synthesis

“…Upon encountering a template lesion or a difficult to replicate region from secondary structure or physical impediments, the HiFi Pol will stall ( Marians, 2018 ; Maiorano et al, 2021 ). The HiFi Pol will attempt insertion of a nucleotide opposite the lesion, however it is almost always unsuccessful ( McCulloch and Kunkel, 2008 ).…”

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

“…There is also poorly defined Alt-EJ that can be independent of sequence homology [195]. DNA polymerase theta (Pol θ) is a predominant mediator of the MMEJ pathway (named TMEJ), that generates short insertions and deletions (Figure 2), associated with specific mutational signatures in human cancers [196,201,202].…”

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

“…Polθ can then form dimers, which facilitate the stabilization of synapsed intermediates and perform a bidirectional scanning initiated from the 3 termini to detect internal microhomologies, which can be annealed, thus generating 3 flaps. Polθ itself can remove the 3 flaps [93] and initiate the repair DNA synthesis with poor processivity and frequent aborted synthesis, resulting in a high rate of mutations (Figure 3) [94]. Importantly, the processing of broken DNA ends is essential to orientate the repair processes.…”