Reduced CHMP7 Expression Compromises Telomere Integrity in Mammalian Cells

Highlights: What are the main findings? The reduction in the nuclear ESCRT CHMP7 drives telomeric aberrations. The reduction in the nuclear-envelope-assembly-related factors LEM2 and BAF1 drives telomeric aberrations. What are the implications of the main findings? The ESCRT machinery is interlinked with telomere organization. Fragilization of telomeres can be an effect of mutations in ESCRT-encoding genes. During open mitosis, reassembly of the nuclear envelope requires the coordinated recruitment of the ESCRT machinery, initiated by the chromatin-associated factor BAF1 and the nuclear-envelope-associated factor LEM2. Because telomeres are enriched at the reforming envelope, we investigated whether ESCRT factors contribute to telomere integrity. Reduction in the pivotal nuclear ESCRT factor CHMP7 caused DNA damage, heterochromatin disorganization, and telomere defects, including sister telomere associations and telomere free ends. Extending this analysis, we found that additional ESCRT components, including TSG101, VPS28, CHMP4B, and the ESCRT-associated factor AKTIP/Ft1, also contribute to telomere integrity, although with different strengths. Genetic interaction analyses suggest that CHMP7 converges in a common pathway with CHMP4B and AKTIP/Ft1, while it functions in parallel routes to TNKS1, a telomere-specific regulator of the shelterin TRF1. More genetic analyses indicated that BAF1 and LEM2 contribute to safeguarding of telomeres during nuclear envelope reassembly. Because defects in nuclear envelope dynamics and chromatin–membrane coupling are hallmarks of disorders associated with nuclear deformation and fragility, including aging and cancer, our findings contribute a new angle into these conditions and suggest potential targets for selectively modulating telomere maintenance pathways.