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A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20

Abstract

In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.

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Figure 1: Loss of Smurf2 leads to increased tumorigenicity.
Figure 2: Smurf2 controls the DNA damage response.
Figure 3: Smurf2 controls both chromatin compaction and patterns of histone modification.
Figure 4: Smurf2 controls chromatin compaction through regulation of RNF20.
Figure 5: RNF20 is a direct target of Smurf2 for proteasome-dependent degradation.
Figure 6: The Smurf2-RNF20 relationship is preserved in various human cells and cancer tissues.

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Acknowledgements

We thank M. Anver for pathology services, V. Barr for assistance with microscope, X. Wu for assistance with the microarray experiments, N. Morris for the animal husbandry and N. Teja for assistance with cell culture. We also thank K. Sixt for comments on the manuscript. This research is supported by the Intramural Research Program of the US National Cancer Institute, US National Institutes of Health, Center for Cancer Research. M.Y. was partially supported by the Japan Society for the Promotion of Science grant 21689053.

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M.Y. and Y.T. maintained mouse colonies and generated primary MEFs and mouse dermal fibroblasts. M.Y., S.Y.C. and Y.E.Z. observed and analyzed the spontaneous tumor formation in mice. S.S.B. performed karyotyping analyses. Y.E.Z. analyzed the microarray data. M.B. performed all other experiments described in the manuscript. M.B. and Y.E.Z. conceived of the study, analyzed the data and wrote the paper.

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Correspondence to Ying E Zhang.

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Blank, M., Tang, Y., Yamashita, M. et al. A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nat Med 18, 227–234 (2012). https://doi.org/10.1038/nm.2596

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