Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Orphan nuclear receptors (NRs) are linked to telomerase-negative cancers utilizing the alternative lengthening of telomeres (ALT) mechanism.
• The precise role of orphan NRs in activating ALT remains largely unknown.

Purpose of the Study:

• To investigate the mechanism by which telomere association of orphan NRs triggers ALT activation.
• To explore the therapeutic potential of targeting orphan NRs and ALT-associated PML bodies.

Main Methods:

• Demonstration of telomeric tethering of orphan NRs in human fibroblasts.
• Analysis of ALT activity markers including DNA synthesis, sister chromatid exchange, and C-circle generation.
• Investigation of the role of zinc finger protein 827, ATRX-DAXX complex, and PML in ALT induction.
• Assessment of arsenic trioxide's effect on ALT in cell lines and mouse xenografts.

Main Results:

• Telomeric tethering of orphan NRs induces de novo ALT activity, including APB formation and telomere DNA synthesis.
• Overexpression of orphan NRs enhances ALT phenotypes, while depletion inhibits ALT.
• Orphan NRs initiate ALT via zinc finger protein 827 and cooperate with ATRX-DAXX complex deficiency.
• PML depletion or arsenic trioxide treatment inhibits ALT induction, and arsenic trioxide reduces ALT activity in vivo.

Conclusions:

• Orphan NRs are key initiators of ALT, functioning through PML body formation and chromatin alterations.
• PML body formation is essential for orphan NR-induced ALT activation.
• Arsenic trioxide effectively inhibits ALT activity, presenting a potential therapeutic strategy for ALT-cancers.