Telomeres are critical for genome stability as they protect chromosome ends from degradation and fusion by cellular DNA repair processes. In non-malignant somatic cells, telomeres undergo progressive shortening after DNA replication, which eventually results in replicative senescence and checkpoint-driven cell death, a phenomenon, which plays a key role in the ageing of the organism. In contrast, tumour cells are able to counteract telomere attrition, and thus achieve replicative immortality, by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination.
We have recently identified the protein SLX4IP as a novel regulator of genome maintenance in human cells. We found that SLX4IP is critical to the control of telomere recombination specifically in ALT-positive tumour cells. We discovered that SLX4IP specifically engages with ALT telomeres (Figure 1) and uniquely interacts with both the SMX resolvasome and the BTR complex, which catalyze recombination intermediate resolution and dissolution, respectively. While SLX4IP is dispensable for telomere maintenance in ALT-negative cells, its loss in ALT-positive cells causes a telomere hyper-recombination phenotype, which is further exacerbated by the co-depletion of the SMX component SLX4 (Figure 2). The combined deficiency of SLX4IP and SLX4 leads to the accumulation of entangled telomere clusters and is synthetic lethal. Strikingly, the detrimental effect of the combined loss of SLX4 and SLX4IP in ALT-positive cells can be rescued by removing the RecQ helicase BLM. Together, our data suggests that SLX4IP controls telomere recombination by counteracting promiscuous BLM activity, and thus ensures the appropriate processing of ALT telomeres by the SMX resolvasome.
Using SLX4IP as a focal point, we now aim to understand
- how this protein and its associated factors ensure genome stability in non-ALT cells,
- how their dysfunction may contribute to genome instability-triggered and ageing-associated diseases such as cancer and neurodegeneration,
- whether they can be exploited to develop personalized disease treatment approaches.