Abstract
SummaryCancer 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.
Highlights
Genome stability is essential for cells to function properly and to ensure the survival of the organism
We found that GFPtagged SLX4IP weakly accumulates at microlaser-induced DNA damage tracks (Figure S1A)
Endogenous SLX4IP showed weak co-localization with the DNA damage marker g-H2AX in cells treated with the DNA inter-strand crosslinking agent mitomycin C (MMC) (Figures S1B and S1C) but not in cells treated with the topoisomerase I inhibitor camptothecin (CPT) (Figures S1D and S1E)
Summary
Genome stability is essential for cells to function properly and to ensure the survival of the organism. The second mechanism, known as alternative lengthening of telomeres (ALT), extends telomeres by upregulating homologydirected recombination pathways (Bryan et al, 1995, 1997; Dunham et al, 2000; Lundblad and Blackburn, 1993; Shay and Bacchetti, 1997). ALT-positive tumors account for approximately 10%–15% of all tumors and are prevalent in tumors of mesenchymal origin (Heaphy et al, 2011b; Henson and Reddel, 2010). These ALT cancers are mostly associated with a poor prognosis because of their complex karyotype and lack of targeted therapies (Dilley and Greenberg, 2015)
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