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.
journal_name
Mol Celljournal_title
Molecular cellauthors
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,Boulton SJdoi
10.1016/j.molcel.2019.07.010subject
Has Abstractpub_date
2019-10-03 00:00:00pages
27-43.e11issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(19)30540-4journal_volume
76pub_type
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