期刊
MOLECULAR CELL
卷 76, 期 1, 页码 27-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.07.010
关键词
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资金
- Francis Crick Institute
- European Molecular Biology Organization (EMBO)
- Institut National Du Cancer (INCA) [PLBIO 2016-159]
- National Center for Advancing Translational Sciences, NIH, through Boston University Clinical and Translational Science Institute (BU-CTSI) [1UL1TR001430]
- National Institute of General Medical Sciences (NIGMS) [T32GM008541]
- Francis Crick Institute - Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- European Research Council (ERC) [ERC-2017-ADG-742437]
- Wellcome Trust
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.
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