PARP inhibition prevents escape from a telomere-driven crisis and inhibits cell immortalisation.

ABSTRACT

Telomeric crisis is the final replicative barrier to cell immortalisation; it is characterised by genome instability and cell death and is triggered when telomeres become critically short and are subjected to fusion. Pre-cancerous lesions, or early stage cancers, often show signs of a telomere crisis, suggesting that escape from telomere crisis is a prerequisite for disease progression. Telomeric crisis therefore represents an attractive, and as yet unexplored, opportunity for therapeutic intervention. Here, we show that two clinically approved PARP inhibitors, selectively eliminate human cells undergoing a telomere-driven crisis. Clonal populations of a colorectal cancer cell line (HCT116), or the plasma cell leukaemia cell line (JJN-3), expressing a dominant-negative telomerase, entered a telomere-driven crisis at defined population doubling points and telomere lengths. The addition of the PARP inhibitors, olaparib or rucaparib prevented these cells from escaping crisis. PARP inhibition did not alter cellular proliferation prior to crisis, rates of telomere erosion or the telomere length at which crisis was initiated, but affected repair of eroded telomeres, resulting in an increased in intra-chromosomal telomere fusion. This was accompanied by enhanced DNA damage checkpoint activation and elevated levels of apoptosis. We propose that PARP inhibitors impair the repair of dysfunctional telomeres and/or induce replicative stress at telomeres to inhibit escape from a telomere crisis. This is the first demonstration that a drug can selectively kill cells experiencing telomeric crisis. We propose that this type of drug, which we term 'crisolytic', has the potential to eliminate pre-cancerous lesions and tumours exhibiting short dysfunctional telomeres.