The ends of linear chromosomes are protected from DNA repair by a number of protein factors, six of which form a multiprotein complex dubbed Shelterin. Among Shelterin's constituents is POT1 (protection of telomeres 1) — a DNA-binding protein — which interacts with a single-stranded, G-rich overhang. Two groups have knocked out POT1 in mice to show that it is required for telomere integrity and genome stability, contributing to our understanding of the distinct roles of Shelterin components.

Hockemeyer et al. and Wu et al. found that, unlike most organisms, the mouse has two Pot1 paralogues: Pot1a and Pot1b. Whereas Wu et al. focused on generating a Pot1a knockout mouse, Hockemeyer et al. created a knockout for each of the paralogues and discovered that each has a distinct function. This finding has implications for using the mouse as a model of human telomere biology because the human genome contains a single Pot1 locus.

So what are the functions of POT1a and POT1b? Pot1a knockout results in embryonic lethality, but Pot1b knockout mice are viable and fertile. The role of POT1 in telomere protection from DNA repair was assessed by looking at the formation of cytologically visible foci of DNA response factors at the telomeres of knockout mice. In the absence of both proteins, telomere protection is lost in 70–80% of nuclei; this proportion falls to 30% when only Pot1a is deleted, whereas Pot1b does not have an effect on its own (which is surprising in view of the telomere structure in this strain; see below). The relationship between POT1a and POT1b in repressing the DNA damage signal is not simple, because overexpressing POT1a or POT1b in Pot1a−/− cells results in different protection levels.

Hockemeyer et al. found that, unlike the loss of Pot1a, loss of Pot1b resulted in excessively long Gstrand overhangs. By crossing Pot1b knockout mice with those that lack functional telomerase, the authors showed that POT1b functions at the telomere independently of the telomerase. Wu et al. found that deleting Pot1a resulted in an increase in telomere length.

Both groups report interesting genome integrity phenotypes associated with Pot1 deletion. Hockemeyer et al. showed that Pot1a alone can prevent telomeric fusions, for which Pot1b can only partially compensate. Loss of Pot1a also leads to endoreduplication. Wu et al. saw numerous chromosome breaks, fusions and fragments in cells lacking Pot1a. Their data also indicate that POT1a has an important role in repressing homologous recombination at telomeres.

Interestingly, the two groups reported different proliferation phenotypes for cells that lack Pot1a: whereas Hockemeyer et al. saw no apparent growth defects, Pot1a loss led to p53-dependent replicative senescence in the hands of Wu et al. In the absence of p53, Pot1a−/− cells bypass this growth defect. These differences remain to be reconciled. Nevertheless, by dissecting POT1 function, both studies demonstrate that different components of Shelterin have distinct functions in protecting chromosome ends. By showing that the functions of the mouse POT1 paralogues seem to have diverged, Hockemeyer et al. also raise the possibility that evolution might have tinkered with the solution to a fundamental problem in chromosome biology more than had been expected.