Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics

Abstract

Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.

Translesion DNA polymerases in eukaryotes: what makes them tick?

“…Furthermore, mutations introduced by error-prone enzymes during bypass synthesis might promote secondary tumor formation and contribute to the acquisition of drug resistance. Both these mechanisms have been demonstrated in cell lines and in mice (Korzhnev and Hadden, 2016; Lange et al , 2011; Maga and Hubscher, 2008; Salehan and Morse, 2013; Xie et al , 2010). Therefore, suppression of the TLS pathway during chemotherapy can be used to enhance drug efficacy, prevent development of secondary neoplasia, and sensitize otherwise drug resistant tumor cells to anticancer treatment (Korzhnev and Hadden, 2016).…”

“…Both these mechanisms have been demonstrated in cell lines and in mice (Korzhnev and Hadden, 2016; Lange et al , 2011; Maga and Hubscher, 2008; Salehan and Morse, 2013; Xie et al , 2010). Therefore, suppression of the TLS pathway during chemotherapy can be used to enhance drug efficacy, prevent development of secondary neoplasia, and sensitize otherwise drug resistant tumor cells to anticancer treatment (Korzhnev and Hadden, 2016). However development of new potentially fruitful treatment strategies should be approached with caution, so that the beneficial effects of TLS incapacitation would not be overpowered by the life-threatening unbalancing of the overall genomic stability, which may actually cause an acceleration of carcinogenesis.…”

“…A surge of interest in this topic is illustrated by the fact that it has been the focus of numerous recent review articles (Jansen et al , 2015; Knobel and Marti, 2011; Korzhnev and Hadden, 2016; Lange et al , 2011; Maga and Hubscher, 2008; Makridakis and Reichardt, 2012; Tomasso et al , 2014). Uncontrolled error-prone nucleotide incorporation during TLS results in excessive accumulation of mutations that can lead to the transformation of normal cells to a malignant state.…”

N2‐Substituted 2′‐Deoxyguanosine Triphosphate Derivatives as Selective Substrates for Human DNA Polymerase κ

“…More recently, specialized polymerases that are over expressed in tumors have been the target of inhibition studies. [7] Identification of nucleotide analogs as selective substrates or inhibitors for specific polymerases is challenging because all polymerases utilize the four cononocial dNTPs, and correct base pairing is mostly dependent on the polymerase recognizing Watson-Crick geometry. Recently, engineered polymerases were utilized to create a modifed nucleotide that can recognize a carcinogen-modified DNA template, [8] and expanded size dNTPs (dxNTPs) have been shown to have some selectivity for human DNA polymerase θ.…”

Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein−Protein Interaction

“…As such, small molecule inhibitors of TLS are emerging as a promising new class of adjuvant agents that could reduce both the dose of genotoxic agents and the associated toxic side effects of first-line therapies, as well as avert chemoresistance. 8 …”