A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres

Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol lambda) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol lambda, strongly affects the survival of ALT cells. In vitro, Pol lambda can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol lambda. Pol lambda associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol lambda in the maintenance of telomeres by the ALT mechanism.

Automated summary

This study reveals that silencing human DNA polymerase (Pol lambda) in ALT cells represses ALT activity and induces telomeric stress, while replication stress in the absence of Pol lambda strongly affects the survival of ALT cells. Additionally, Pol lambda can promote annealing of telomeric repeats and is regulated by TERRA and replication protein A, with the POT1/TPP1 heterodimer stimulating Pol lambda activity.