1. SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.
- Author
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Panier S, Maric M, Hewitt G, Mason-Osann E, Gali H, Dai A, Labadorf A, Guervilly JH, Ruis P, Segura-Bayona S, Belan O, Marzec P, Gaillard PL, Flynn RL, and Boulton SJ
- Subjects
- Animals, Bone Neoplasms genetics, Bone Neoplasms pathology, Carrier Proteins genetics, Cell Proliferation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Mice, Knockout, Mice, SCID, Osteosarcoma genetics, Osteosarcoma pathology, Protein Binding, Protein Interaction Domains and Motifs, RecQ Helicases genetics, Recombinases genetics, Recombinases metabolism, Signal Transduction, Telomere genetics, Telomere pathology, Bone Neoplasms enzymology, Carrier Proteins metabolism, Osteosarcoma enzymology, RecQ Helicases metabolism, Telomere metabolism, Telomere Homeostasis
- Abstract
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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