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.

RETRACTED: A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells

“…Furthermore, we propose that the delay in the release of telomeric TRF2 after exposure to cytotoxic PARPi reflects the time needed to inactivate the PARP1-MRE11-BRCC3-MMS21 sumoylation pathway, desumoylate TRF2, and destabilize telomeric TRF2. Although PARP1 has not previously been recognized to stabilize telomeric TRF2, it is present at the TRF2-containing eroded telomeres of TERT-deficient, ALT-independent cells (56), suppresses the emergence of telomeredefective cells from telomere-driven crisis (57), is hyperactivated by ATRX depletion (58), and works in tandem with MRE11 to recruit TRF2 to sites of nontelomeric, laser-induced DNA damage (59). Our data, along with the previous studies, suggest that TRF2 relies on the interaction of PARP1 with MRE11 and on previously undescribed PARP1-MRE11-driven pathways, to suppress the lethal fusion of telomeres maintained by the ALT mechanism.…”

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

“…The modified TRPM2 function may suggest disturbed signaling between TRPM2 and PARPs at the transcript level, which increases the expression of polymerases. Numerous studies have reported that overexpression of PARP genes in turn is associated with uncontrolled cell proliferation, increased DNA repair ability, and increased telomerase activity which is associated with cell immortalization [36].…”

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects

“…Finally, since TH5487 had a low impact on U2OS viability, we combined TH5487 with a heterogeneous set of conventional chemotherapeutic agents and BER inhibitors, looking for potential synergies in telomerase negative (U2OS) or positive transformed human cell lines (BJ-TERT, HCT116, NTUB1). Despite poly ADP ribose polymerase inhibitors (PARPi) targeting BER are known to induce replicative stress at telomeres that leads to telomere crisis 45 , we did not find any synergy or additive effect with TH5487 (Table 1 ). Indeed, it has been recently described that olaparib toxicity in BRCA1-depleted cells is attenuated by treatments with a ROS scavenger, hypoxia, or OGG1 inhibitor 46 , suggesting that toxicity derived from PARPi in cancer cells might be attenuated by BER inhibition.…”