Telomeric replication stress: the beginning and the end for alternative lengthening of telomeres cancers

Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. Telomeric DNA comprises terminal tracts of G-rich tandem repeats, which are inherently difficult for the replication machinery to navigate. Structural aberrations that promote activation of the alternative lengthening of telomeres (ALT) pathway of telomere maintenance exacerbate replication stress at ALT telomeres, driving fork stalling and fork collapse. This form of telomeric DNA damage perpetuates recombination-mediated repair pathways and break-induced telomere synthesis. The relationship between replication stress and DNA repair is tightly coordinated for the purpose of regulating telomere length in ALT cells, but has been shown to be experimentally manipulatable. This raises the intriguing possibility that induction of replication stress can be used as a means to cause toxic levels of DNA damage at ALT telomeres, thereby selectively disrupting the viability of ALT cancers.

Automated summary

Telomeres are protein structures that cover the ends of chromosomes. The DNA at telomeres contains repetitive sequences that are difficult to replicate. Structural abnormalities at ALT telomeres increase replication stress, leading to stalling and collapse of replication forks. This DNA damage stimulates recombination-mediated repair and break-induced telomere synthesis. The coordination between replication stress and DNA repair regulates telomere length in ALT cells, and can be manipulated experimentally. Inducing replication stress may selectively disrupt the viability of ALT cancer cells.