Loss of Tumor Suppressor STAG2 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 STAG2 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 STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 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. STAG2 silencing in normal human cells which 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 STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur.

Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium

“…STAG2 encodes a subunit of the cohesin complex, has been associated with aneuploidy, and is a tumor suppressor gene ( Kim et al., 2012 , Hill et al., 2016 ). STAG2 loss results in prolonged association of telomeric repeats during the cell cycle and that this may result in genomic rearrangements ( Daniloski and Smith, 2017 ). To explore whether the biased behavior of STAG2-deficient stem cells arises directly or whether it could be mediated by subsequent elevated genomic instability, we performed simulations.…”

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach

“…The disruption of TADs and the removal of cohesin or CTCF binding sites result in abnormal DNA domain topology, thus leading to gene expression dysregulation 14 23–25. Cohesin is also essential for genome integrity as it controls fork replication speed,26 27 promotes DNA repair by homologous recombination,28–32 safeguards telomere stability33 34 and recruits proteins involved in G2/M checkpoints 35 36. DNA damage response and gene transcription are intimately associated via cohesin.…”

Granular cell astrocytoma: an aggressive IDH‐wildtype diffuse glioma with molecular genetic features of primary glioblastoma

“…STAG2 is located in the X chromosome , and encodes a protein subunit component of the cohesin complex that participates in sister chromatid separation during cell division . STAG2 alterations lead to aneuploidy and telomere recombination and are encountered in a variety of tumor types including bladder cancer, melanoma, and Ewing sarcoma . In the TCGA datasets, mutations in STAG2 were present in 17/794 predominantly IDH wildtype gliomas (http://www.cbioportal.org).…”