Analysis of tankyrase 1 and tankyrase 2 in human cells and mouse models.

摘要

Regulation of telomere length and protection of chromosome ends are two critical telomere functions that are essential in maintaining genome stability. Tankyrase 1 and 2 are telomeric poly(ADP-ribose) polymerases (PARPs) that function as positive regulators of telomere length in human cells. In addition, tankyrase 1 is required after DNA replication to resolve sister telomeres prior to mitosis. Using human cells and mouse models, we sought to better understand the functions of tankyrase 1 and 2. Tnks2 PARP-domain deleted mice had a small mouse phenotype, but no defects in telomere length maintenance or capping. Similarly, Tnks1-deficient mice had no defects in telomere length maintenance or capping. Double depletion of Tnks1 and Tnks2 led to embryonic lethality in mice, indicating essential but redundant roles. By contrast, the effects of tankyrase 1 or 2 depletion in human cells were more dramatic. Tankyrase 2 depletion led to cell death, whereas tankyrase 1 depletion led to DNA damage and a senescence-like phenotype. Further analysis of tankyrase 1 depleted cells revealed (in addition to persistent telomere cohesion) a high frequency of sister telomere fusions, which were generated by DNA Ligase IV-dependent nonhomologous end-joining of cohered sister telomeres. Thus, removal of sister telomere cohesion by tankyrase 1 is crucial for telomere protection and genomic stability in human cells.