Biological and Therapeutic Relevance of Nonreplicative DNA Polymerases to Cancer

Abstract

Apart from surgical approaches, the treatment of cancer remains largely underpinned by radiotherapy and pharmacological agents that cause damage to cellular DNA, which ultimately causes cancer cell death. DNA polymerases, which are involved in the repair of cellular DNA damage, are therefore potential targets for inhibitors for improving the efficacy of cancer therapy. They can be divided, according to their main function, into two groups, namely replicative and nonreplicative enzymes. At least 15 different DNA polymerases, including their homologs, have been discovered to date, which vary considerably in processivity and fidelity. Many of the nonreplicative (specialized) DNA polymerases replicate DNA in an error-prone fashion, and they have been shown to participate in multiple DNA damage repair and tolerance pathways, which are often aberrant in cancer cells. Alterations in DNA repair pathways involving DNA polymerases have been linked with cancer survival and with treatment response to radiotherapy or to classes of cytotoxic drugs routinely used for cancer treatment, particularly cisplatin, oxaliplatin, etoposide, and bleomycin. Indeed, there are extensive preclinical data to suggest that DNA polymerase inhibition may prove to be a useful approach for increasing the effectiveness of therapies in patients with cancer. Furthermore, specialized DNA polymerases warrant examination of their potential use as clinical biomarkers to select for particular cancer therapies, to individualize treatment for patients. Antioxid. Redox Signal. 18, 851-873.

Translesion DNA polymerases in eukaryotes: what makes them tick?

“…Among the many reasons for TLS deregulation are changes in the expression of the polymerase catalyzing lesion bypass; mutations in the TLS polymerase itself reducing its fidelity or improving its competitiveness; and modulation of the interactions of a TLS polymerase with its protein partners. An increase in genomic instability, a hallmark of cancer, has been linked to the (i) hindering of the normal replicase operation, (ii) imbalances in expression of DNA polymerases, (iii) lack of a relatively accurate TLS “polymerase of choice” responsible for bypassing a particular lesion in normal cells, or (iv) outcompeting the polymerase by another, less accurate enzyme [reviewed in (Beagan and McVey, 2016; Ghosal and Chen, 2013; Guo et al , 2013; Jansen et al , 2015; Knobel and Marti, 2011; Lange et al , 2011; Loeb and Monnat, 2008; Luo et al , 2012; Makridakis and Reichardt, 2012; Nicolay et al , 2012b; Parsons et al , 2013; Pillaire et al , 2014; Sharma et al , 2013; Shcherbakova and Fijalkowska, 2006; Sweasy et al , 2006; Yousefzadeh et al , 2014)].…”

Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

“…Long-range interactions were treated with the particle mesh Ewald method (41). After initial isothermal-isobaric trajectory at 10K to adjust the density of the system near 1.0 g/cm 3 , a 20-ns constant volume/ constant temperature (T = 300K) equilibrium simulation with the sequentially decreasing harmonic constraint force constants (from 50 to 0.1 kcal/mol/nm) applied to the protein, DNA, and metal ions in the crystallographic structure ensures that the system coordinates represent a precatalytic state. Before QM/MM calculations, we optimized several configurations selected from MD simulations and used the lowest energy system as the starting configuration for the reaction path calculation; other configurations are within 3 kcal/mol to this lowest energy conformation.…”

“…Because DNA polymerases are an attractive chemotherapeutic target, chainterminating nucleoside drugs are often used in a strategy of blocking DNA synthesis (3)(4)(5). However, drug resistance to chain-terminating agents is influenced by the ability of a stalled DNA polymerase to remove chain-terminating nucleotides through pyrophosphorolysis (6)(7)(8).…”

Modulating the DNA polymerase β reaction equilibrium to dissect the reverse reaction

“…Chain-terminating nucleoside drugs are often utilized in an attempt to block DNA synthesis 3,4 . However, drug resistance to chain-terminating agents can be correlated with an ability of stalled DNA polymerase to remove these nucleotides through pyrophosphorolysis 5–7 .…”