Telomerase is said to prevent "end-to-end fusion" of chromosomes.
My question is threefold:
- What is an "end-to-end fusion"?
- How does Telomerase prevent end-to-end fusions?
- Why do end-to-end fusions cause problems in cells?
An end-to-end fusion is the result of two chromosome ends fused together. This happens when telomeres (repeated sequences at the ends of chromosomes) lose their protective telomere-binding proteins. In mammalian cells, loss of TRF2 (telomere repeat-binding factor 2) leads to chromosome fusions.
Here is an example of how it looks with metaphasic chromosomes (the DNA is stained in blue and the telomeres are stained in pink; picture from Rai et al, 2016). The left panel shows normal chromosomes, the right panel shows end fusions upon depletion of TRF2.
What causes chromosome fusions in such situations is the DNA double-strand break (DSB) repair machinery, which is normally repressed by telomere proteins (mainly by TRF2; see van Steensel et al, 1998). In mammalian cells, telomere-binding proteins are collectively called the shelterin complex (they literally shelter chromosome ends; see de Lange, 2005).
Telomerase doesn't repress the DSB repair machinery directly. Because of the structure of telomeres (a single-stranded 3' overhang) and of the way replication is primed, linear chromosomes cannot be fully replicated and will gradually shorten at each replication. When telomeres become critically short, they don't recruit enough telomere-binding proteins and therefore fail to repress the DSB repair machinery. Telomerase, when expressed and activated, maintains the length of telomeres in replicating cells at each replication (by adding repeated sequences complementary of the RNA template that is a component of the telomerase holoenzyme), providing binding sites for telomere-binding proteins, and thus indirectly contributes to the repression of the DSB repair machinery.
End-to-end fusions cause problems in cells in part because fused chromosomes will likely not segregate properly during mitosis and meiosis. The resulting daughter cells end up with altered ploidies that can be severe enough to prevent cell viability.
de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19: 2100-2110 https://doi.org/10.1101/gad.1346005
Rai R, Chen Y, Lei M & Chang S (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7: 10881 https://doi.org/10.1038/ncomms10881
van Steensel B, Smogorzewska A & de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401-413 https://doi.org/10.1016/S0092-8674(00)80932-0