Different outcomes of telomere-dependent anaphase bridges

Abstract

Chromosomal instability occurs early in the development of cancer and may represent an important step in promoting the multiple genetic changes required for the initiation and/or progression of the disease. Telomere erosion is one of the factors that contribute to chromosome instability through end-to-end chromosome fusions entering BFB (breakage-fusion-bridge) cycles. Uncapped chromosomes with short dysfunctional telomeres represent an initiating substrate for both pre- and post-replicative joining, which leads to unstable chromosome rearrangements prone to bridge at mitotic anaphase. Resolution of chromatin bridge intermediates is likely to contribute greatly to the generation of segmental chromosome amplification events, unbalanced chromosome rearrangements and whole chromosome aneuploidy. Accordingly, telomere-driven instability generates highly unstable genomes that could promote cell immortalization and the acquisition of a tumour phenotype.

Rb1 Haploinsufficiency Promotes Telomere Attrition and Radiation-Induced Genomic Instability

“…The presence of telomeric DNA within both acrocentric fragments and anaphase bridges in irradiated cells suggests involvement of the shortened telomeres. This is consistent with the formation and breakage of end-to-end fusions between chromosomes capped by truncated telomeres or between truncated telomeres and radiation-induced double-strand breaks (23,24). Such fused chromosomes would be subject to physical tension at the next cytokinesis, causing random breakage with the potential to form chromatin bridges and micronuclear fragments during the next cell cycle (25).…”

“…The loss of one copy of the Rb1 gene, and the resultant haploinsufficiency, impaired the ability of the cells to handle radiation-induced stress by either G 2 -M arrest or senescence. Impairment of both of these Rb1-dependent DNA damagerestoring functions that follow cell stress (23,26,27) may explain the persistence polyploid cells generated by the increased genomic instability. The concomitant loss of the canonical cell-cycle regulatory function of Rb1 would prevent cells with chromosomal damage from entering G 1 -S arrest and subsequently entering the apoptosis or senescence pathways.…”

Chromosomal instability and cancer: a complex relationship with therapeutic potential

“…Dozens of gene products are involved in ensuring chromosome segregation fidelity, and therefore it is not surprising that defects in multiple mechanisms that lead to errors in chromosome segregation appear in cancer (20). These include faulty sister chromatid cohesion (21), defective centrosome duplication (22)(23)(24), telomere dysfunction (25), hyperactive or hypoactive spindle assembly checkpoint (SAC) (26)(27)(28), and overly stable attachments of microtubules to chromosomes (29,30). Most of these mechanisms converge to produce lagging chromosomes during anaphase (5,24,29,30).…”

Cytokinesis-Block Micronucleus Assay Adapted for Analyzing Genomic Instability of Human Mesenchymal Stem Cells

“…Anaphase bridges often break [101,103], resulting in chromosomal alterations, such as amplifications, translocations, or deletions, which are biomarkers of genomic instability in malignant cells and used for diagnostic purposes in oncology [104]. After anaphase bridge breakage and fusion of uncapped chromosome ends, in the next interphase, breakage-fusion-bridge cycles initiate and propagate through several divisions, generating more alterations, such as aneuploidy, polyploidy, and genetic mutations [105][106][107][108]. Calado et al [109] provided direct clinical evidence that telomere shortening in hematopoietic progenitor cells, followed by breakage-fusion-bridge cycles, increases predisposition to malignant transformation in patients with aplastic anemia.…”