Trapping PARP-DNA complexes – anti-cancer drug screening

PARPs (Poly ADP ribose polymerases) are found in the nucleus of the cell and they are involved in SSB repair (single-strand DNA breaks). PARP is known to bind damaged DNA through its N-terminal zinc finger domain. Subsequently it starts to synthesize a poly (ADP-ribose) chain which serves as a signal for other DNA-repairing enzymes.

SYNTHETIC_ LEATHALITY

Fig. 1: Principle of synthetic lethality

PARP inhibitors are considered to be promising  candidates as anti cancer drugs (recently Olaparib, the first drug directed against PARP1, has been approved by the European commission). One of the reasons is that some tumors are more dependent on PARP than regular cells. These cancer cells are mutated in BRCA1 or BRCA2 – both genes which are involved in key DNA damage repair mechanisms. In healthy cells PARPs can function as a kind of back-up system and let the cells survive even without functional BRCA gene products. When PARPs are inhibited the cells do not possess any functional SSB repair mechanism anymore and are bound to die (Fig. 1; take a look at PARPs as cancer drug targets – first EC-approved drug to learn more about the concept of “synthetic lethality”). [Read more…]