Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells

Abstract

SUMMARY Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

“…We previously described numerical (ranging from near diploid to near tetraploid) and structural chromosome aberration in thyroid cancer cell lines established from Thrb PV/PV mice (46). The presence of Thrb PV/PV thyrocyte populations with 40 or more telomere signals in several age groups is consistent with the notion that both aneuploid and/ or tetraploid cells have tumorigenic properties (47)(48)(49). Aneuploidy is common in many human cancers (50,51) and serves as independent prognostic factor for clinical outcome of numerous cancer types, including differentiated and undifferentiated/anaplastic thyroid cancer (52)(53)(54).…”

Senescence from G2 arrest, revisited

“…91 Subsequent work by the same team has shown that tetraploidization triggered by permanently damaged telomeres promotes tumorigenic transformation of mouse cells. 92 The most recent evidence implicating the G2 exit program in senescence has come from 3 publications that also took advantage of FUCCI imaging system. The Nakanishi group showed that replicative senescence or exposure to various senescence-causing stimuli induces p53-dependent mitotic bypass (referred to as mitotic skipping), entailing irreversible cell cycle arrest in the 4N G1 state and accumulation of the senescent markers p16 and b-galactosidase.…”

“…59,93 Similarly, in aging p53/pRbdeficient cells, extensive telomere erosion induces crisis with massive cell death and tetraploidization through endoreplication or mitotic failure. 92 tag, the Medema group investigated the role of p21-dependent cyclin B1 nuclear retention in senescence induction in G2-arrested cells upon IR. 95 They elegantly confirmed and extended previous observations 58,69 and pinpointed this event as the first step in triggering the G2 exit program, resulting in permanent cell cycle withdrawal (Fig.…”

Telomere in Aging and Age-Related Diseases

“…(108,112,113) The genomic alterations included whole genome reduplication, chromothripsis and kataegis. (114)(115)(116) Telomere fusions can occur between different chromosomes or between sister chromatids after DNA replication, thus leading to different outcomes. (4) BFB cycles generally can lead to three outcomes related to cancer: LOH, non reciprocal translocations and gene amplification.…”