PhD Student National Taiwan University, Taiwan (Republic of China)
Abstract: Telomeres are repetitive sequences located at the ends of chromosomes, protecting genomic integrity. In most somatic cells where telomerase is inactive, telomeres shorten with each cell replication. Critically short telomeres lead to proliferation arrest, senescence, or cell death. Poly(ADP-ribose) polymerase 1 (PARP1) is a major sensor of DNA breaks and plays important roles in DNA repair. In a previous study, we demonstrated that PARP1 inhibition elongated telomeres in telomerase deficient human induced pluripotent stem cells (hiPSCs), implicating that PARP1 inhibition mediated telomere elongation is not through the activation of telomerase. Here, we hypothesize that PARP1 inhibition has senolytic effect, i.e., eliminating cells of shorter telomeres, on hiPSCs, thus leading to the observed longer telomeres in surviving cells. In this study, we treated wildtype hiPSCs with PARP1 inhibitor for three days. Our data showed that such treatment did not activate telomerase activity, but significantly reduced the cells’ proliferation rate and caused the S-phase arrestment. Markers of senescence, including P16, P21, and IL-6, are upregulated, while the apoptosis-related marker BCL2 demonstrated a downregulation trend in the inhibitor treated cells. Importantly, the telomere lengths are longer after the inhibitor treatment. These data suggest that PARP1 inhibition may selectively eliminate cells with critically short telomeres.
Funding Source: National Science and Technology Council, Taipei, Taiwan, R.O.C. Grant number NSTC 113-2313-B-002-011
