Loss of Tumor Suppressor <i>STAG2</i> Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells.

Abstract

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The <i>STAG2</i> gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how <i>STAG2</i> loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in <i>STAG2</i> mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in <i>STAG2</i> mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. <i>STAG2</i> silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of <i>STAG2</i> could promote tumorigenesis by extending the period during which tumor-driving mutations occur. <i>Cancer Res; 77(20); 5530-42. ©2017 AACR</i>.