Alternative Lengthening of Telomeres Requires a Specialized Replisome

In approximately 10% to 15% of cancers, telomeres are maintained by homologous recombination–dependent alternative lengthening of telomeres (ALT) instead of telomerase upregulation. However, the mechanism by which DNA damage triggers telomere elongation in mammalian cells is not well understood. Dilley and colleagues developed methods to isolate and quantify nascent telomeres after the generation of telomere double strand breaks (DSB). These approaches revealed that telomere specific DSBs induced unidirectional synthesis of long tracts of telomeric DNA in a process they termed break-induced telomere synthesis. Break-induced telomere synthesis occurred by an alternative DNA replication complex, which lacked many of the canonical replisome components. Break-induced telomere synthesis was also independent of DNA damage responsive kinases ATR and ATM, as well as the homologous recombination protein RAD51. Break-induced telomere synthesis required the Polδ replicative DNA polymerase for synthesis of both the C- and G-rich strands and the Polδ accessory subunit POLD3. ALT telomere synthesis was independent of several other polymerases including Polϵ, Polα, Polη, and Polζ, and the canonical replisome associated helicase complex MCM2-7. Altogether, these findings indicate that a minimal Polδ containing replisome is responsible for break-induced telomere synthesis. Mechanistically, proliferating cell nuclear antigen (PCNA) was loaded by replication factor C (RFC) at damaged telomeres and interacted with POLD3 to recruit the Polδ complex to ALT telomeres, indicating that RFC–PCNA functions as a telomere damage sensor. Consistent with these findings, POLD3 was essential for Polδ complex stabilization, and depletion of POLD3 reduced ALT telomere synthesis. Collectively, these data indicate that a noncanonical replisome is involved in break-induced telomere synthesis at ALT telomeres, thereby differentiating ALT from S-phase replication and suggesting the potential for targeting ALT in cancer.

Dilley RL, Verma P, Cho NW, Winters HD, Wondisford AR, Greenberg RA. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 2016;539:54–8.

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