Abstract
WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC) and it accelerates cell proliferation in NSCLC. However, the detailed mechanism underlying the role of WDR79 in the proliferation of NSCLC cells remains unclear. Here, we report the discovery of a molecular interaction between WDR79 and USP7 and show its functional significance in linking the Mdm2-p53 pathway to the proliferation of NSCLC cells. We found that WDR79 colocalized and interacted with USP7 in the nucleus of NSCLC cells. This event, in turn, reduced the ubiquitination of Mdm2 and p53, thereby increasing the stability and extending the half-life of the two proteins. We further found that the functional effects of WDR79 depended upon USP7, because the knockdown of USP7 resulted in their attenuation. Finally, we demonstrated that WDR79 promoted the proliferation of NSCLC cells via USP7. Taken together, our findings reveal a novel molecular function of WDR79 and may lead to broadly applicable and innovative therapeutic avenues for NSCLC.
Highlights
The WDR79 gene on chromosome 17p13 encodes both an antisense transcript (WRAP53α) for p53 stabilization[1] and a protein (WDR79, WRAP53, WRAP53β or TCAB1) with six individual with a tryptophan-aspartic acid (WD)-repeat domains via the use of alternative transcriptional start sites
We report a new molecular process in which WDR79 interacts with USP7 to modulate the stability of Mdm[2] and p53, which promotes the proliferation of non-small cell lung cancer (NSCLC) cells
We found that USP7 was co-immunoprecipitated by anti-Flag antibody in WDR79overexpressing cells but not in negative control cells transfected with the same amount of empty vector (Figure 1c)
Summary
The WDR79 gene on chromosome 17p13 encodes both an antisense transcript (WRAP53α) for p53 stabilization[1] and a protein (WDR79, WRAP53, WRAP53β or TCAB1) with six individual WD-repeat domains via the use of alternative transcriptional start sites. As a tumour suppressor protein, p53 function is abnormal in over 50% of human cancers.[25,26] In normal unstressed cells, p53 is a very unstable protein with a short half-life and maintained at a low level due to its rapid degradation via the ubiquitin-dependent proteasome pathway.[27,28] in response to diverse cellular stress, such as DNA damage, hypoxia, telomeres shortening and oncogene activation, p53 is rapidly stabilized because its degradation is blocked, which results in cell cycle arrest, apoptosis and cellular senescence.[29] Mdm[2] is the E3 ubiquitin ligase of p53 and binds to p53 to promote its degradation.[30] Recent studies have revealed that USP7 is involved in the regulation of the p53-Mdm[2] pathway. Our findings reveal a novel role of WDR79 in the proliferation of NSCLC cells and could pinpoint a new mechanism by which WDR79 and USP7 functionally interact to modulate the Mdm2-p53 pathway
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