Characterization of PAXIP1 in alternative lengthening of telomeres

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. About 10% - 15% of human cancers rely on the recombination-based alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet the underlying molecular mechanism remains incompletely understood. Here we found the chromatin binding protein PAXIP1 as a novel ALT regulator and identified PAGR1 as its main functional protein partner. Mechanistically, we show that PAXIP1/PAGR1 complex complements with the PML nuclear body scaffold protein to promote ALT-directed telomere maintenance, independently from its MLL3/MLL4 complex-associated transcriptional function. We propose PAXIP1/PAGR1 complex as a functional component of break-induced telomere repair. Overall design: SAOS2 cells were lentivirally infected to express Cas9. Specific guide RNAs targeting PAXIP1 and/or PML were stably expressed in these cells.