Emerging Roles of E3 Ubiquitin Ligase Smurf2 in Cancer and Beyond

Recent studies unveiled the E3 ubiquitin ligase Smurf2 as an influential cellular factor, whose expression and activities are highly pertinent to carcinogenesis. We showed that the genetic ablation of Smurf2 in mouse tissues triggers a series of cascading events, and creates the “mutator phenotype”, which under the stress of aging leads to carcinogenesis. Mechanistic studies revealed that Smurf2 operates as an essential regulator of DNA damage response, gene expression, and genomic integrity maintenance, spanning through and interlocking these components. The results also suggested that these Smurf2 activities are associated with its ability to regulate chromatin structure landscape through RNF20. Recently, we identified another intriguing mechanism associated with Smurf2 tumor suppressor function. We found that Smurf2 operates as a molecular editor of DNA topoisomerase IIα, protecting this enzyme from proteasomal degradation, thereby preventing the formation of anaphase DNA bridges, a major cause of chromosomal translocations. Our second line of investigation led to elucidation of Smurf2 as a bona fide negative regulator of A-type nuclear lamins, in particular of lamin A and its disease-associated form progerin, whose expression underlies the development of a devastating premature aging syndrome – Hutchinson-Gilford Progeria Syndrome (HGPS). Remarkably, in addition to HGPS, progerin accumulation has been associated with a physiological aging and cancer. This association suggests that the targeting of A-lamins in cancer might be a promising direction to eradicate tumor cells. In summary, these and other recent findings exposed Smurf2 as a key cellular factor involved in the regulation of pivotal processes in mammalian cells.