Researchers identify telomere-based mechanism which turns mutant cells into aggressive cancers.


Telomere dysfunction has been proposed as a key event that causes cancer progression. According to this model, progressive telomere shortening results in telomere dysfunction and end-to-end chromosomal fusions. The resulting dicentric chromosomes undergo cycles of breakage-fusion-bridge (BFB) and lead to gross chromosomal rearrangements. At this stage, reactivation of telomerase prevents further telomere dysfunction and allows cancer cells to proliferate indefinitely.  Now, a study from researchers at The Scripps Research Institute (TSRI) shows how a telomere-based gene mutation found in several human cancers, including leukemia, gliomas and melanoma, promotes the growth of aggressive tumours.  The team state that their research also suggests a possible way to kill these kinds of tumours by targeting an important enzyme.  The opensource study is published in the journal Cell Reports.

Previous studies show that mutations affecting the telomere-binding protein protection of telomeres 1 (POT1) have been reported in chronic lymphocytic leukemia, familial melanoma, cardiac angiosarcoma, glioma, mantle cell lymphoma, and parathyroid adenoma.  This protein normally forms a protective cap around the ends of chromosomes, known as telomeres, stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.  POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme, called ATR, which triggers programmed cell death.  The current study shows that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway and uncovers a role for defective telomere replication during tumourigenesis.

The current study utilises a mouse model to show that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.  Results show that the cells no longer have the mechanism for dying, so the mice developeed really aggressive thymic lymphomas.  Data findings show that P53, a well-known tumour suppressor gene, overrides the protective cell death response initiated by ATR.

Results show that without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. Data findings show that these mutant cells go on to proliferate and become aggressive tumours.  The group state that all cells, even cancer cells, will die if they have no ATR and since tumours with mutant POT1 already have low ATR levels, they hypothesize that a medicine that knocks out the remaining ATR could kill tumours without affecting healthy cells.

The team surmise that their findings define a role for POT1 inactivation in the onset of thymic lymphomas, and shows that inhibition of POT1 causes replication defects at telomeres resulting in telomere fragility, replication fork stalling, as well as genomic instability.  They go on to add that this suggests a role for defective telomere replication during tumourigenesis.  For the future, the researchers state that their study shows by looking at basic biological questions, the global medical community can potentially find new ways to treat cancer; they now plan to investigate this new therapeutic approach.

Source: The Scripps Research Institute (TSRI)

 

Exacerbated Genome Instability in Tumors Derived from POT1p53Cd2 Mice.  Representative metaphase spreads from thymic lymphomas with the indicated genotype. The telomeres are in green (peptide nucleic acid [PNA] probe) and the chromosomes in red (DAPI). The highlighted chromosomes in the right images show examples of telomeres fusions (white arrow) and fragile telomeres (red arrow).  Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.  Denchi et al 2016.

Exacerbated Genome Instability in Tumors Derived from POT1p53Cd2 Mice. Representative metaphase spreads from thymic lymphomas with the indicated genotype. The telomeres are in green (peptide nucleic acid [PNA] probe) and the chromosomes in red (DAPI). The highlighted chromosomes in the right images show examples of telomeres fusions (white arrow) and fragile telomeres (red arrow). Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis. Denchi et al 2016.

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