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.
| Original language | English |
|---|---|
| Pages (from-to) | 227-234 |
| Number of pages | 8 |
| Journal | Nature Medicine |
| Volume | 18 |
| Issue number | 2 |
| DOIs | |
| State | Published - 8 Jan 2012 |
| Externally published | Yes |
Bibliographical note
Funding Information: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.
