Telomere Loss Provokes Multiple Pathways to Apoptosis and Produces Genomic Instability inDrosophila melanogaster

Abstract

Telomere loss was produced during development of Drosophila melanogaster by breakage of an induced dicentric chromosome. The most prominent outcome of this event is cell death through Chk2 and Chk1 controlled p53-dependent apoptotic pathways. A third p53-independent apoptotic pathway is additionally utilized when telomere loss is accompanied by the generation of significant aneuploidy. In spite of these three lines of defense against the proliferation of cells with damaged genomes a small fraction of cells that have lost a telomere escape apoptosis and divide repeatedly. Evasion of apoptosis is accompanied by the accumulation of karyotypic abnormalites that often typify cancer cells, including end-to-end chromosome fusions, anaphase bridges, aneuploidy, and polyploidy. There was clear evidence of bridge-breakage-fusion cycles, and surprisingly, chromosome segments without centromeres could persist and accumulate to highcopy number. Cells manifesting these signs of genomic instability were much more frequent when the apoptotic mechanisms were crippled. We conclude that loss of a single telomere is sufficient to generate at least two phenotypes of early cancer cells: genomic instability that involves multiple chromosomes and aneuploidy. This aneuploidy may facilitate the continued escape of such cells from the normal checkpoint mechanisms.

Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica

“…Secondly, it has been suggested that cell competition could be a mechanism to remove aneuploid cells. 27,28 As there is p53-independent removal of aneuploid cells, 27,28 our findings are consistent with cell competition as the mechanism.…”

“…[22][23][24][25][26] Cell competition may be a means to eliminate certain categories of aneuploid cells. 27,28 Seventy-nine ribosomal protein genes, sixty-six of which are haploinsufficient Minute loci, are distributed throughout the Drosophila genome. 2 Copy number changes to parts of the genome are likely to perturb relative dose of Rp/+ genes, and those that reduce Rp gene dose could be subject to cell competition.…”

“…This suggests cell competition can eliminate some aneuploid cells even after DNA damage responses have ceased. [27][28][29] In humans, heterozygosity for multiple different Rp mutations causes Diamond Blackfan Anemia. 30 Accumulation of ribosomal assembly intermediates or of unassembled ribosomal proteins in these genotypes activates p53, for example through the binding of the p53 ubiquitin ligase Mdm2 by RpL11 or RpL5.…”

Healing of Euchromatic Chromosome Breaks by Efficient de novo Telomere Addition in Drosophila melanogaster

“…Flies carrying eyFLP (Newsome et al 2000) and a chromosome with adjacent inverted FRTs, including the Dc3(FrTr61A5)1A and Dc3(FrTr100E3)1A chromosomes, produce dicentric chromosomes in the cells of the developing eyeantennal disc, resulting in a reduced rate of eclosion (because many die as pharate adults) and adults with small rough eyes (data not shown). This is likely a consequence of the cell death that follows dicentric chromosome breakage (Ahmad and Golic 1999;Titen and Golic 2008). When we tested 49 of the w Sb putative TD chromosomes with eyFLP, all progeny had eyes with a wild-type phenotype, confirming that they no longer carried inverted FRTs.…”

Adapting to life at the end of the line

“…20,21 Studies of Drosophila larval somatic tissues showed that the loss of a single telomere could trigger a spectrum of responses: chromosome end fusions, dicentric chromosome breakage, aneuploidy and other signs of genome instability also associated with dysfunctional telomeres in mammals and yeasts.…”