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The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins

Nature Structural & Molecular Biology volume 14, pages 581–590 (2007)Cite this article

Abstract

Most cancer cells activate telomerase to elongate telomeres and achieve unlimited replicative potential. Some cancer cells cannot activate telomerase and use telomere homologous recombination (HR) to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres to PML bodies (termed APBs). Here, we show that the SMC5/6 complex localizes to APBs in ALT cells and is required for targeting telomeres to APBs. The MMS21 SUMO ligase of the SMC5/6 complex SUMOylates multiple telomere-binding proteins, including TRF1 and TRF2. Inhibition of TRF1 or TRF2 SUMOylation prevents APB formation. Depletion of SMC5/6 subunits by RNA interference inhibits telomere HR, causing telomere shortening and senescence in ALT cells. Thus, the SMC5/6 complex facilitates telomere HR and elongation in ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins.

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Figure 1: The SMC5/6 complex localizes to PML nuclear bodies.
Figure 2: Inhibition of the SMC5/6 complex decreases telomere recombination (T-SCE).
Figure 3: The SMC5/6 complex is required for APB formation.
Figure 4: MMS21 SUMOylates the core telomere-binding proteins.
Figure 5: MMS21-induced SUMOylation of telomere-binding proteins is required for APB formation.
Figure 6: Inhibition of the SMC5/6 complex results in telomere shortening and cellular senescence.
Figure 7: Two proposed models for how MMS21-induced shelterin SUMOylation promotes telomere length maintenance in ALT cells.

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Acknowledgements

We thank W. Wright (University of Texas Southwestern Medical Center) for the SUSM1, SW26 and SW39 cell lines, D. Chen (University of Texas Southwestern Medical Center) for complementary DNAs encoding the telomere-binding proteins, and S. Chang (M.D. Anderson Cancer Center) for G5 Terc−/− Wrn−/− Rasv12 MEF ALT cells. We also thank members of our laboratory and the laboratories of D. Chen and W. Wright for helpful discussions. This work is supported by grants from the W.M. Keck Foundation (to H.Y.) and the Welch Foundation (to H.Y.), and by a US National Institutes of Health Pharmacological Sciences Training Grant (to P.R.P.).

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  1. Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, 75390-9041, Texas, USA

    Patrick Ryan Potts & Hongtao Yu

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P.R.P. and H.Y. designed the research. P.R.P. performed the experiments and analyzed the results. P.R.P. and H.Y. wrote the paper.

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Correspondence to Hongtao Yu.

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Supplementary information

Supplementary Fig. 1

SMC5–SMC6 localizes to PML bodies in telomerase–positive HeLa cells, but does in ALT cells (PDF 82 kb)

Supplementary Fig. 2

SMC5–SMC6 localizes to PML bodies in SW26 ALT but not in SW39 telomerase-positive cells (PDF 53 kb)

Supplementary Fig. 3

Cohesin complex does not localize to PML bodies (PDF 77 kb)

Supplementary Fig. 4

MMS21 sumoylates components of the shelterin complex (PDF 90 kb)

Supplementary Fig. 5

TRF2 sumoylation is required for TRF2 recruitment to PML bodies (PDF 90 kb)

Supplementary Fig. 6

Inhibition of the SMC5–SMC6 complex results in telomeric shortening (PDF 104 kb)

Supplementary Table 1

Knockdown of the SMC5–SMC6 complex in ALT cells results in telomere abnormalities (PDF 7 kb)

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Potts, P., Yu, H. The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. Nat Struct Mol Biol 14, 581–590 (2007). https://doi.org/10.1038/nsmb1259

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