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MUS81 promotes common fragile site expression

Nature Cell Biology volume 15, pages 1001–1007 (2013)Cite this article

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Abstract

Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers1. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis2. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81–EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81–EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81–EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.

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Figure 1: Replication fork restart is defective in MUS81-depleted cells.
Figure 2: MUS81 localizes to CFS loci and is required for fragile site breakage after low-dose aphidicolin treatment.
Figure 3: MUS81-depleted cells show excessive fragile-site-associated chromosome mis-segregation.
Figure 4: MUS81-depleted cells generate excessive CFS-associated UFBs and 53BP1 nuclear bodies.
Figure 5: Model for the role of MUS81–EME1 in preserving genome integrity at CFSs.

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Acknowledgements

Work in the authors’ laboratory is supported by Cancer Research UK, The Nordea Foundation, The Association of International Cancer Research, The Danish Cancer Society, and the National Natural Science Foundation of China.

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Author notes

  1. Kok Lung Chan

    Present address: Present address: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK,

  2. Songmin Ying, Sheroy Minocherhomji and Kok Lung Chan: Joint first authors

Authors and Affiliations

  1. Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK

    Songmin Ying, Kok Lung Chan, Timea Palmai-Pallag & Ian D. Hickson

  2. Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, and Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China

    Songmin Ying

  3. Institute of Clinical Pathology and Department of Pathology, Medical College of Shantou University, Shantou 515031, China

    Songmin Ying

  4. Department of Cellular and Molecular Medicine, Nordea Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark

    Sheroy Minocherhomji, Wai Kit Chu, Theresa Wass, Hocine W. Mankouri, Ying Liu & Ian D. Hickson

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Contributions

S.Y., S.M., K.L.C., T.P-P., W.K.C., T.W. and Y.L. performed experimental work and data analysis. S.Y., S.M., K.L.C., H.W.M.,. Y.L. and I.D.H. planned the project and analysed data. S.Y., S.M., H.W.M., Y.L. and I.D.H. wrote the manuscript.

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Correspondence to Songmin Ying or Ian D. Hickson.

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Ying, S., Minocherhomji, S., Chan, K. et al. MUS81 promotes common fragile site expression. Nat Cell Biol 15, 1001–1007 (2013). https://doi.org/10.1038/ncb2773

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