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

In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here, we show that genomic ablation of Smurf2, a HECT-domain E3 ubiquitin ligase, results in dysregulation of DNA damage response and genomic stability, culminating to increased susceptibility to various types of cancers in aged mice. We demonstrate that Smurf2 regulates histone H2B monoubiquitination as well as histone H3 tri-methylation at K4 and K79 by targeting RNF20 to proteasomal degradation in both mouse and human cells. We further show that Smurf2 and RNF20 are co-localized 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.