Nucleolin is a ubiquitously expressed protein and participates in many important 
biological processes, such as cell cycle regulation and ribosomal biogenesis. 
The activity of nucleolin is regulated by intracellular localization and 
post-translational modifications, including phosphorylation, methylation, and 
ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of recently 
verified forms of post-translational modifications and exerts various effects on 
the target proteins. In the studies reported here, we discovered SUMOylational 
modification of human nucleolin protein at Lys-294, which facilitated the mRNA 
binding property of nucleolin by maintaining its nuclear localization. In 
response to arsenic exposure, nucleolin-SUMO was induced and promoted its 
binding with gadd45α mRNA, which increased gadd45α mRNA stability and protein 
expression, subsequently causing GADD45α-mediated cell death. On the other hand, 
ectopic expression of Mn-SOD attenuated the arsenite-generated superoxide 
radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced 
apoptosis by reducing GADD45α expression. Collectively, our results for the 
first time demonstrate that nucleolin-SUMO at K294R plays a critical role in its 
nucleus sequestration and gadd45α mRNA binding activity. This novel biological 
function of nucleolin is distinct from its conventional role as a 
proto-oncogene. Therefore, our findings here not only reveal a new modification 
of nucleolin protein and its novel functional paradigm in mRNA metabolism but 
also expand our understanding of the dichotomous roles of nucleolin in terms of 
cancer development, which are dependent on multiple intracellular conditions and 
consequently the appropriate regulations of its modifications, including 
SUMOylation.