Putting injured cells to sleep

Each time a cell divides, chromosome ends shorten owing to a quirk in the DNA replication process. Protein-capped repetitive sequences called telomeres provide an essential buffer against degradation of the chromosome ends.

Telomeric uncapping causes cell division to shut down via a process known as senescence, which is mediated at least in part by the protein p53. However, new findings from a team led by Curtis Harris at the US National Cancer Institute in Bethesda, Maryland have shown that p53 can also actively trigger this uncapping process in response to genetic damage¹.

Exposure to DNA-damaging conditions stimulates production of p53. Harris and colleagues found that this ‘up-regulation’ is associated with reduced levels of TRF2, a key telomere-binding protein, in cultured cells. Under these conditions, p53 also induces the expression of Siah1; this enzyme, ubiquitin ligase, selectively marks other proteins for rapid degradation; TRF2 appears to be among its targets. Pre-malignant adenoma cells exhibiting p53-associated senescence also showed increased Siah1 and decreased TRF2 levels relative to healthy cells, indicating that this regulatory pathway is also active in the human body.

The researchers conclude that this represents a potentially important feedback loop that drives rapid telomere uncapping in damaged cells, shunting them towards senescence as a protective measure against uncontrolled cancerous growth.