Telomeric SUMO level influences the choices of APB formation pathways and ALT efficiency

Abstract

Many cancers use an alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT telomeric DNA synthesis occurs in ALT telomere-associated PML bodies (APBs). However, the mechanisms by which APBs form are not well understood. Here, we monitored the formation of APBs with time-lapse imaging employing CRISPR knock-in to track the promyelocytic leukemia (PML) protein at endogenous levels. We found APBs form via two pathways: telomeres recruit PML proteins to nucleate PML bodies de novo, or telomeres fuse with preformed PML bodies. Both nucleation and fusion of APBs require interactions between SUMO and SUMO interaction motifs (SIMs). Moreover, APB nucleation is associated with higher levels of SUMOs and SUMO-mediated recruitment of DNA helicase BLM, resulting in more robust telomeric DNA synthesis. Finally, further boosting SUMO levels at telomeres enhances APB nucleation, BLM enrichment, and telomeric DNA synthesis. Thus, high SUMO levels at telomeres promote APB formation via nucleation, resulting in stronger ALT activity.