Investigating the Role of Smurf2 in the Regulation of Cohesin Protein Complex

Authors

• MR Molla
• CH Stuelten
• T Xiao
• Y Tang
• JH Shin
• KC Birendra
• YE Zhang

Abstract

Cohesin, a multiprotein complex composed of SMC1, SMC3, and Rad21 is indispensable for chromosomal architecture maintenance, particularly in sister chromatid cohesion, DNA repair, and gene expression regulation. Cohesin is known to be ubiquitinated, although the mechanism, regulation, and effects of cohesin ubiquitination remain poorly defined. Smad ubiquitin regulatory factor 2 (Smurf2), a member of the HECT domain E3 ubiquitin ligase family, as a pivotal regulator. Smurf2 was initially recognized as a negative regulator of transforming growth factor- (TGF-) and bone morphogenetic protein (BMP) signaling, but recent studies identified its function to regulate genomic stability and carcinogenesis. Therefore, our study provides a focused examination of Smurf2's role in modulating SMC1, SMC3, and Rad21 within the cohesin complex. We report here that Smurf2 is a novel cohesin-interacting protein identified by mass spectrometry analysis of dual-affinity purifications. Subsequent immunoprecipitation/Western blots and immunofluorescence staining confirmed the endogenous interaction and colocalization of Smurf2 and cohesin complex in MCF10A cells. Our study also revealed that the WW and hect domains of Smurf2 are crucial for cohesin binding and Smurf2 negatively regulates cohesin protein levels in MCF10A cells. Furthermore, we also found that Smurf2 and cohesin protein complex colocalized at the mitotic spindle. According to the above results, we summarize that Smurf2 may modulate the assembly or stability of the cohesin complex through direct interactions with its components. By influencing the formation or stability of the cohesin complex, Smurf2 could impact chromosomal processes such as genomic stability and gene regulation.

Scientific Focus Area: Cancer Biology

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