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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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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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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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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DOI: https://doi.org/10.1038/ncb2773
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