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SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

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.

SUBMITTER: Panier S

PROVIDER: S-EPMC6863466 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

Panier Stephanie S Maric Marija M Hewitt Graeme G Mason-Osann Emily E Gali Himabindu H Dai Anqi A Labadorf Adam A Guervilly Jean-Hugues JH Ruis Philip P Segura-Bayona Sandra S Belan Ondrej O Marzec Paulina P Gaillard Pierre-Henri L PL Flynn Rachel L RL Boulton Simon J SJ

Molecular cell 20190822 1

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 ...[more]

PMID: 31447390

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Project description:BackgroundTo ensure replicative immortality in cancer, telomeres must be maintained through activation of telomere maintenance mechanisms (TMMs) that are dependent on telomerase or the alternative lengthening of telomeres (ALT) pathway. Although TMM pathways have traditionally been considered to be mutually exclusive, ALT hallmarks have been identified in cancers defined as being telomerase-positive, supporting TMM coexistence. In castration-resistant prostate cancer (CRPC), in vitro models were thought to be universally dependent on telomerase as the primary TMM; however, CRPC models with androgen receptor (AR) loss demonstrate ALT hallmarks with limited telomerase activity and require ALT-associated PML bodies (APBs) for sustained telomere maintenance. The TMM coexistence in AR-negative CRPC is reliant on the ALT regulator protein, SLX4IP.MethodsTo identify the regions of SLX4IP responsible for the induction of APBs and telomere preservation in CRPC models, five 3xFLAG-tagged SLX4IP constructs were designed and stably introduced into parental C4-2B, DU145, and PC-3 cells. Once generated, these cell lines were interrogated for APB abundance and SLX4IP construct localization via immunofluorescence-fluorescence in situ hybridization (IF-FISH) and coimmunoprecipitation experiments for telomeric localization. Similarly, PC-3 cells with endogenous SLX4IP knockdown and SLX4IP construct introduction were interrogated for APB abundance, telomere length preservation, and senescent rescue.ResultsHere, we define the N-terminus of SLX4IP as being responsible for the promotion of the ALT-like phenotype of AR-negative CRPC models. Specifically, the N-terminus of SLX4IP was sufficient for promoting APB formation to a similar degree as full-length SLX4IP across CRPC cell lines. Additionally, APB promotion by the N-terminus of SLX4IP rescued telomere shortening and senescent induction triggered by SLX4IP knockdown in AR-negative CRPC cells. Moreover, APB formation and telomere maintenance were dependent on the ability of the N-terminus to direct SLX4IP localization at telomeres and APBs.ConclusionsThese findings identify the role of the uncharacterized ALT regulator SLX4IP in the promotion of TMM coexistence to perpetuate replicative immortality in CRPC in vitro.

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SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

Publications

SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

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