Down-regulation of cancer-associated gene CDC73 contributes to cellular senescence

Dysregulated gene expression is another important contributor in explaining cancer-related phenotypes in addition to mutations. Cellular senescence is a mechanism for the prevention of cancer and thus it is important to understand the regulation of gene expression in senescence due to its potential in anti-cancer therapy. Here, we found that CDC73, which encodes the cell division cycle 73 and acts as a tumor suppressor, was unexpectedly up-regulated in several cancer types but down-regulated in a variety of senescent cells. Importantly, depletion of CDC73 could induce senescence-associated phenotypes in both normal and cancer cells, with an increase in p21 expression. In terms of molecular mechanism, alternative polyadenylation (APA)-mediated 3′ untranslated region (3′ UTR) lengthening explained, at least in part, the decreased CDC73 expression in senescent cells because longer 3′ UTR had a higher rate of RNA degradation compared to the shorter one. Our work discovered that post-transcriptional down-regulation of CDC73 contributed to cellular senescence.