Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates.

The cell cycle is key to life. After decades of research, it is unclear whether any parts of this process have yet to be identified. Fam72a is a poorly characterized gene and is evolutionarily conserved across multicellular organisms. Here, we have found that Fam72a is a cell-cycle-regulated gene that is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C, respectively. Functionally, Fam72a directly binds to tubulin and both the Aα and B56 subunits of PP2A-B56 to modulate tubulin and Mcl1 phosphorylation, which in turn affects the progression of the cell cycle and signaling of apoptosis. Moreover, Fam72a is involved in early responses to chemotherapy, and it efficiently antagonizes various anticancer compounds such as CDK and Bcl2 inhibitors. Thus, Fam72a switches the tumor-suppressive PP2A to be oncogenic by reprogramming its substrates. These findings identify a regulatory axis of PP2A and a protein member in the cell cycle and tumorigenesis regulatory network in human cells.