PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Abstract

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…4). The roles of various PARPs include DNA repair (modulated chiefly by PARP-1 to -3), regulation of gene transcription (PARP-1, -2, and structurally different macroPARPs: PARP-9, -14, -15) [128], RNA processing in the nucleus and cytoplasm (PARP-1, -7, -10, -12 to -15, tankyrase-1) [19], cellular RNA transport (probable role of vault PARP and PARP-10) [1], cellular transport of proteins (mainly PARP-16) [1], and telomere maintenance (somewhat ambiguously including PARP-1, tankyrase-1 and possibly tankyrase-2) [174,177].…”

G-quadruplexes Significantly Stimulate Pif1 Helicase-catalyzed Duplex DNA Unwinding

“…In recent years, the notion that G4s may play critical and beneficial functions in cells has emerged (20). G4s formed from the G-rich telomeric overhang will prevent DNA damage surveillance mechanisms from recognizing telomeres as a DNA damage signal (21)(22)(23)(24). Furthermore, it has long been recognized that G4 motifs are very abundant in promoter regions and at the 5Ј end of the first intron (25)(26)(27).…”

Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer

“…In this regard, growing evidence shows that G4 ligands selectively impair the growth of cancer cells without affecting the viability of normal cells pointing out these molecules as possible drug candidates for future clinical application (8,9). This evidence gains further support by the marked antitumoral activity showed by some of those compounds (BRACO-19, RHPS4, and telomestatin) in different in vivo models both as single agents and in combination with conventional or targeted anticancer agents (10)(11)(12)(13)(14)(15). However, none of the other G4 ligands developed so far has made it through the drug discovery pipeline due to poor drug-like properties and/or selectivity profile (16,17).…”