SUMOylation negatively regulates the stability of CHFR tumor suppressor

Abstract CHFR ubiquitin ligase acts as a checkpoint upon DNA damage and its functional inactivation is one of key characteristics of tumor development and metastasis. Despite the crucial role in maintaining genome integrity and cell cycle progression, little is known how CHFR stability is regulated. Here, we showed that CHFR is covalently modified by SUMO-1 at lysine 663 and subsequently destabilized by ubiquitin–proteasome system. While CHFR K663R substitution mutation does not alter its subcellular localization, SUMOylation-defective CHFR K663R -stable cells exhibit substantial growth suppression due to the increased stability of CHFR K663R . Moreover, protein level of CHFR, not CHFR K663R , is rapidly declined under SUMOylation-promoting conditions, and SENP2 deSUMOylating enzyme reverses its SUMO-modification. Collectively, we demonstrated that CHFR stability is regulated by SUMOylation-dependent proteasomal degradation. Therefore, our study underscores the importance of CHFR SUMOylation as a new regulatory mechanism of CHFR and highlights the emerging role of SUMOylation in modulating protein stability.