Helicases as prospective targets for anti-cancer therapy

Abstract

It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint.

Fig. 1. Structures of DNA interstrand cross-links introduced by chemotherapeutic agents

Panel A, chloroethylnitrosurea. Panel B, mitomycin C. Panel C, 8-methoxypsoralen. Panel D, platinum.

Fig. 1. Structures of DNA interstrand cross-links introduced by chemotherapeutic agents

Panel A, chloroethylnitrosurea. Panel B, mitomycin C. Panel C, 8-methoxypsoralen. Panel D, platinum.

Fig. 2. Chemical structures of the chemotherapy drugs camptothecin, etoposide, and doxorubicin

Fig. 3. Chemical structure of the chemotherapy agent and topoisomerase I inhibitor Irinotecan

Fig. 4. Chemical structure of the HSP90 inhibitor Geldanamycin

Fig. 5. The single-stranded DNA binding protein RPA increases WRN helicase processivity in a specific manner by a direct protein interaction

Panel A, schematic of DNA unwinding reaction catalyzed by WRN helicase with RPA coating ssDNA that is generated by duplex unwinding. Panel B, DNA and protein interactions of RPA and WRN helicase. Note that the physical interaction between RPA70 and the WRN acidic repeats is required for RPA stimulation of WRN helicase activity on long duplex DNA substrates.

Fig. 6. Telomeric DNA structures that RecQ helicases are proposed to act upon

Panel A, Intra-telomeric (t-loop) and inter-telomeric structures that are created through strand invasion of the 3′ telomeric overhang into the duplex region of the telomere. Panel B, secondary planar structure of G-quadruplex DNA, stabilized by Hoogsteen hydrogen bonds, that may form in the G-rich 3′ ssDNA overhangs of telomeres. Panel C, G-quadruplex interactive compound and potential anti-cancer drug Telomestatin.