Abstract
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.
Highlights
Telomeres are evolutionarily conserved G-rich sequences at the distal ends of linear chromosomes
Cancers that rely on the alternative lengthening of telomeres (ALT) pathway of telomere maintenance constitute approximately 10–15% of all cancers, with this proportion rising substantially in tumours of mesenchymal and neuroepithelial origin [155]
Cancers that use the ALT pathway have an intrinsic reliance on replication stress to direct DNA repair pathways to the telomeres to achieve homology-directed telomere extension
Summary
Telomeres are evolutionarily conserved G-rich sequences at the distal ends of linear chromosomes. Telomeres present an exceptional challenge to the replication machinery This is the cumulative result of the terminal repetitive G-rich sequence content of telomeres, the necessity for constant structural remodelling of telomeric DNA into t-loops, displacement loops (D-loops), DNA/RNA hybrids and G-quadruplex structures during replication and transcription, the constitutive heterochromatic organization of telomeric chromatin, and the engagement of opposing telomere length regulation mechanisms. This is further compounded by a reliance on subtelomeric origins of replication. We discuss telomeric replication, the homeostasis between replication stress and repair at ALT telomeres, and how tipping this balance can impact ALT activity and ALT cell viability
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