Hitting the bull's eye: Novel directed cancer therapy through helicase‐targeted synthetic lethality

Abstract

Designing strategies for anti-cancer therapy have posed a significant challenge. One approach has been to inhibit specific DNA repair proteins and their respective pathways to enhance chemotherapy and radiation therapy used to treat cancer patients. Synthetic lethality represents an approach that exploits pre-existing DNA repair deficiencies in certain tumors to develop inhibitors of DNA repair pathways that compensate for the tumor-associated repair deficiency. Since helicases play critical roles in the DNA damage response and DNA repair, particularly in actively dividing and replicating cells, it is proposed that the identification and characterization of synthetic lethal relationships of DNA helicases will be of value in developing improved anti-cancer treatment strategies. In this review, we discuss this hypothesis and current evidence for synthetic lethal interactions of eukaryotic DNA helicases in model systems.Keywords synthetic lethality; helicase; cancer therapy; DNA repair; anti-cancer drug Cells exposed to DNA damage have multiple pathways in order to cope with the stressed condition. DNA repair is believed to represent a good target for enhancing cancer treatment strategies that are based on chemotherapy drugs or radiation that induce death of rapidly proliferating cells. There is a growing interest in synthetic lethality of compensating DNA repair pathways as a strategy to target cancer therapies based on the genetic background of the tumor. Since helicases play an integral role in the DNA damage response, it seems reasonable that this particular class of proteins may be one of the optimal bull's eye targets for cancer therapy based on synthetic lethality (Fig. 1). Specifically, compensatory repair pathways mediated by DNA helicases are a priority for further studies. Research in the basic sciences has demonstrated and characterized synthetic lethal interactions of eukaryotic DNA helicases. This work is likely to serve as a foundation for the development of anti-cancer therapies that utilize small molecule helicase inhibitors or antagonists to helicase gene expression such as RNA interference.

Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress

“…Our laboratory has taken a particular interest in directed cancer therapy through helicase-targeted synthetic lethality (24). Tumor cells with DNA repair deficiencies, either BRCA or mismatch repair, might be particularly vulnerable to therapeutic strategies targeting WRN.…”

Unique Helicase Determinants in the Essential Conjugative TraI Factor from Salmonella enterica Serovar Typhimurium Plasmid pCU1

“…Alternatively, equation 2 could be used to yield a value for K D as previously described (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)53):…”

“…As a result, helicases are key players in a wide variety of DNA and RNA metabolic processes, such as recombination, chromatin remodeling, and DNA transport (4)(5)(6). Most recently, helicases have emerged as potential therapeutic targets for diseases ranging from cancer to Gram-positive bacterial infections (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Classified into six superfamilies, superfamily 1 and 2 (SF1 and SF2) helicases are the most similar, sharing up to seven conserved sequence motifs and core RecA-like folds (1)(2)(3).…”

DNA Helicases Associated with Genetic Instability, Cancer, and Aging

“…Use of small molecules to target human helicases for inhibition (or activation) in a cell-based model system is a novel approach to the problem of assigning specific helicase functions in vivo. In addition to the new insight to the roles of helicases in DNA damage response and repair to prevent age-associated phenotypes, this work will also be informative for the development of anticancer strategies which target DNA repair proteins/processes [107]. …”