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How spontaneous telomeric fusions occur: unravelling new pathways required for end protection

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Insight into telomere regulation

Maintaining chromosomes at constant length is a critical process for the cell. Delineating how this process is regulated is paramount for identifying the determinants of carcinogenesis.

Fundamental Research

Inherently, the mammalian genome replication process cannot copy the very end of each chromosome, resulting in the gradual shortening of the chromosomes. To prevent the loss of genes, mammalian chromosomes possess end regions of repetitive sequence known as telomeres, which prevent the activation of the DNA damage machinery. In contrast, if telomeres become too long, they become unstable and can recombine. Certain cells of the body such as germline cells and stem cells contain telomerase, a highly evolutionary conserved reverse transcriptase, which extends the telomeres of chromosomes. It compensates for the cell's inability to fully replicate the tips of chromosomes. Yet, how telomere elongation is regulated to avoid constant elongation and formation of unstable telomeres remains poorly understood. To address this question, scientists of the EU-funded TELOSCREEN (How spontaneous telomeric fusions occur: unravelling new pathways required for end protection) project utilised Schizosaccharomyces pombe as a model organism. They carried out a transposon-based genetic screen to unravel new proteins required for telomere homeostasis. Results identified the highly-conserved phosphatase Ssu72 as a regulator of telomerase. Scientists observed that Ssu72 mutants exhibited three to five times longer telomeres than wild-type cells as well as checkpoint activation and DNA damage responses. Mutants failed to recruit the single-strand DNA-binding complex that promotes lagging strand synthesis and telomerase inhibition. This clearly indicated a role for Ssu72 in lagging strand synthesis and in the inhibition of telomerase recruitment. Similar results were obtained in human cells, where down-regulation of SSU72 expression induced telomere elongation and cell arrest. Collectively, TELOSCREEN results advance considerably our understanding of telomere regulation and homeostasis. Since cancer cells have active telomerase, long term this information will not only provide insight into the mechanisms of cancer development, but also form the basis for the design of novel anti-cancer strategies.


Telomere, chromosome, telomerase, TELOSCREEN, Ssu72

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