Letter | Published:

Telomere recombination requires the MUS81 endonuclease

Nature Cell Biology volume 11, pages 616623 (2009) | Download Citation

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Abstract

Telomerase-negative cancer cells maintain their telomeres through the alternative lengthening of telomeres (ALT) pathway1,2,3. Although a growing body of evidence demonstrates that the ALT mechanism is a post-replicative telomere recombination process, molecular details of this pathway are largely unknown. Here we demonstrate that MUS81, a DNA structure specific recombination endonuclease, has a key role in the maintenance of telomeres in human ALT cells. We find that MUS81 specifically localizes to ALT-associated promyelocytic leukaemia (PML) nuclear bodies (APBs) and associates with telomeric DNA in ALT cells, which is enriched during the G2 phase of the cell cycle. Depletion of MUS81 results in the reduction of ALT-specific telomere recombination and leads to proliferation arrest of ALT cells. In addition, the endonuclease activity of MUS81 is required for recombination-based ALT cell survival, and the interaction of MUS81 with the telomeric repeat-binding factor TRF2 regulates this enzymatic activity, thereby maintaining telomere recombination. Thus, our results suggest that MUS81 is involved in the maintenance of ALT cell survival at least in part by homologous recombination of telomeres.

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Acknowledgements

We thank R. R. Reddel for ALT cells, and C. H. McGowan for wild-type and mutant MUS81 constructs, the MUS81 antibody and Mus81 +/+ and Mus81−/− MEFs. We thank I. Hickson and J. Roti Roti for proof-reading. This work is supported in part by grants from Concern Foundation to Q.Y. and NIH CA10445/CA123232 to T.K.P. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Author information

Author notes

    • Sicong Zeng

    Current address: Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, Hunan 410078, China.

Affiliations

  1. Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108, USA.

    • Sicong Zeng
    • , Tao Xiang
    • , Tej K. Pandita
    • , Ignacio Gonzalez-Suarez
    • , Susana Gonzalo
    •  & Qin Yang
  2. Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA.

    • Ignacio Gonzalez-Suarez
    •  & Susana Gonzalo
  3. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

    • Curtis C. Harris

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Contributions

S.Z. performed most of the experiments; T.X performed immunoprecipitation-western assays and I.G.S. performed Q-FISH assay; T.K.P, S.G and C.C.H analysed data and Q.Y. planned the project, designed experiments, analysed data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Qin Yang.

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DOI

https://doi.org/10.1038/ncb1867

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