ausblenden:
Schlagwörter:
Animals
Bone Neoplasms/*enzymology/genetics/pathology
Carrier Proteins/genetics/*metabolism
Cell Proliferation
DNA-Binding Proteins/genetics/metabolism
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Humans
Mice, Knockout
Mice, SCID
Osteosarcoma/*enzymology/genetics/pathology
Protein Binding
Protein Interaction Domains and Motifs
RecQ Helicases/genetics/*metabolism
Recombinases/genetics/metabolism
Signal Transduction
Telomere/genetics/*metabolism/pathology
*Telomere Homeostasis
*alt
*blm
*slx4
*slx4ip
*xpf
*cancer
*genome stability
*homologous recombination
*telomere
Zusammenfassung:
Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.
