Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

Abstract

Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development.

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

“…( 84 , 133 ). Non-B DNA loci composed of repeats can pose an obstacle to DNA replicative polymerases, and the observed nucleotide substitution frequencies could reflect processing by low-fidelity, specialized DNA polymerases ( 65 , 66 , 134–136 ) gene conversion and increased DNA damage. Gene conversion is common at cruciform and slipped-strand structures ( 137 ), and could explain the decreased nucleotide substitution frequencies in repeat arms of inverted and direct repeats—particularly for fixed nucleotide substitutions, where multiple rounds of gene conversion might have taken place.…”

“…Replicative polymerases encounter many non-B DNA structures that act as natural impediments to DNA synthesis elongation. Specialized DNA polymerases associated with the replication fork, including Pols eta and kappa, perform highly efficient synthesis through non-B DNA structures (reviewed in ( 56 , 65 , 66 )), and can take over synthesis from stalled replicative polymerases ( 67 ). DNA damage-induced mutagenesis has been associated with non-B structure formation (reviewed in ( 68 )), and damage induced by reactive oxygen species is affected by the inherent structure and local sequence of DNA (reviewed in ( 69 )).…”

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

“…Further insights into the link between replication stress and CIN came from the discovery of the replication stress protection conferred by specialized polymerases that are able to replicate across noncanonical DNA and AT-rich sequences at difficult-to-replicate regions [105,106]. Notably, it was shown that the translesion synthesis DNA polymerase eta is recruited to specific CFSs during the S phase and promotes their timely replication [107].…”

Analysis of DNA Polymerases Reveals Specific Genes Expansion in Leishmania and Trypanosoma spp.

“…Interestingly, non-B structured and difficult-to-replicate DNA regions, are present in eukaryotic genomes: Z-DNA, H-DNA triplex, cruciform, hairpins, and G- tetrads (Wickramasinghe et al, 2015 ; Tsao and Eckert, 2018 ; Stern et al, 2019 ). In mammals, Y-family polymerases have been implicated in replicating these particular regions (Eddy et al, 2014 , 2016 ; Wickramasinghe et al, 2015 ; Quinet et al, 2018 ; Tsao and Eckert, 2018 ). Moreover, a role in DNA replication origin has been recently described (Prorok et al, 2019 ).…”