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Role of mammalian Mre11 in classical and alternative nonhomologous end joining

Nature Structural & Molecular Biology volume 16, pages 814–818 (2009)Cite this article

Abstract

The mammalian Mre11–Rad50–Nbs1 (MRN) complex coordinates double-strand break signaling with repair by homologous recombination and is associated with the H2A.X chromatin response to double-strand breaks, but its role in nonhomologous end joining (NHEJ) is less clear. Here we show that Mre11 promotes efficient NHEJ in both wild-type and Xrcc4−/− mouse embryonic stem cells. Depletion of Mre11 reduces the use of microhomology during NHEJ in Xrcc4+/+ cells and suppresses end resection in Xrcc4−/− cells, revealing specific roles for Mre11 in both classical and alternative NHEJ. The NHEJ function of Mre11 is independent of H2A.X. We propose a model in which both enzymatic and scaffolding functions of Mre11 cooperate to support mammalian NHEJ.

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Figure 1: Mre11 regulates both Xrcc4-dependent and Xrcc4-independent NHEJ.
Figure 2: Mre11 promotes end processing in Xrcc4-independent NHEJ.
Figure 3: The homologous recombination and NHEJ function of Mre11 is at least in part independent of H2A.X.
Figure 4: Model for MRN's functions at a mammalian DSB.

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Acknowledgements

We thank F. Alt, C. Yan and members of the Scully laboratory for helpful discussions, and B. Lopez, D. Ferguson and S. Chang for discussions and for sharing data before publication. We thank J. Chen (Yale University) for antibodies to mouse Brca1. This work was supported by R01s CA095175 and GM073894 and a Leukemia and Lymphoma Society Scholar Award (to R.S.).

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  1. Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Anyong Xie, Amy Kwok & Ralph Scully

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Contributions

A.X. designed and performed the experiments; R.S. participated in the design of the experiments; A.K. assisted on Southern blotting and DNA sequencing; A.X. and R.S. analyzed the data and wrote the manuscript.

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Correspondence to Anyong Xie or Ralph Scully.

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Xie, A., Kwok, A. & Scully, R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16, 814–818 (2009). https://doi.org/10.1038/nsmb.1640

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