DNA polymerase eta: A potential pharmacological target for cancer therapy

Abstract

In the last two decades, intensive research has been carried out to improve the survival rates of cancer patients. However, the development of chemoresistance that ultimately leads to tumor relapse poses a critical challenge for the successful treatment of cancer patients. Many cancer patients experience tumor relapse and ultimately die because of treatment failure associated with acquired drug resistance. Cancer cells utilize multiple lines of self-defense mechanisms to bypass chemotherapy and radiotherapy. One such mechanism employed by cancer cells is translesion DNA synthesis (TLS), in which specialized TLS polymerases bypass the DNA lesion with the help of monoubiquitinated proliferating cell nuclear antigen. Among all TLS polymerases (Pol η, Pol ι, Pol κ, REV1, Pol ζ, Pol μ, Pol λ, Pol ν, and Pol θ), DNA polymerase eta (Pol η) is well studied and majorly responsible for the bypass of cisplatin and UV-induced DNA damage. TLS polymerases contribute to chemotherapeutic drug-induced mutations as well as therapy resistance. Therefore, targeting these polymerases presents a novel therapeutic strategy to combat chemoresistance. Mounting evidence suggests that inhibition of Pol η may have multiple impacts on cancer therapy such as sensitizing cancer cells to chemotherapeutics, suppressing drug-induced mutagenesis, and inhibiting the development of secondary tumors. Herein, we provide a general introduction of Pol η and its clinical implications in blocking acquired drug resistance. In addition; this review addresses the existing gaps and challenges of Pol η mediated TLS mechanisms in human cells. A better understanding of the Pol η mediated TLS mechanism will not merely establish it as a potential pharmacological target but also open possibilities to identify novel drug targets for future therapy.

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

“…The emergence of resistance after initial therapy for cancer patients is almost inevitable and ultimately leads to treatment failure, which remains a significant clinical challenge. 42 Although it is clear that resistant cancer cells often result in more aggressive tumour behaviour, metastasis, recurrence and poor clinical outcomes, 43 it remains unclear how to best treat these resistant cells. Resensitization of therapy‐surviving cells to conventional drugs has been proposed as a promising strategy.…”

DNA Damage Tolerance Pathways in Human Cells: A Potential Therapeutic Target

“…In recent years, several TLS polymerase inhibitors have been reported (187). Examples include indole thiobarbituric acid (ITBA) and its' derivatives (185,186).…”

“…to cisplatin; reduces melanoma tumor volume in mouse model(177,187) NovobiocinPol q Synthetic lethality with olaparib in HR-deficient ovarian cancer cells; tumor regression in mouse model (188) ART558; ART812 Pol q Synthetic lethality with olaparib in HR-deficient colon cancer cells; inhibition of HR-deficient tumor xenografts in rat model(189) …”

Beyond the Lesion: Back to High Fidelity DNA Synthesis

“…The concentrations of TLS Pols are generally kept lower than HiFi Pols to prevent their equilibrium association and low fidelity synthesis. In fact, altered expression of the TLS Pols have been linked with increased mutation rates ( Pavlov et al, 2001 ; Qi et al, 2012 ; Sasatani et al, 2017 ), correlated with various cancers ( O-Wang et al, 2001 ; Albertella et al, 2005b ; Flanagan et al, 2007 ; Wang et al, 2010 ), and give rise to chemotherapeutic resistance ( Saha et al, 2021 ). There is evidence that TLS Pols are cell cycle regulated under normal conditions, peaking in G2 phase to facilitate any required TLS prior to cell division ( Waters and Walker, 2006 ; Plachta et al, 2015 ; Sobolewska et al, 2020 ).…”