The FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle
A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance to response to these new therapies. Here, using data from the Cancer Dependency Map, we identified the poorly-studied factor FAM53C as a new regulator of the G1/S transition. We found that FAM53C is necessary and sufficient for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase inhibited by and directly interacting with FAM53C. DYRK1A kinase inhibition rescues the G1 arrest induced by FAM53C knock-down. Fam53C knockout human cortical organoids also display increased cell cycle arrest and growth defects. Fam53C knockout mice are viable but show defects in body growth, as would be expected for a promoter of cell proliferation. Because DYRK1A dysregulation contributes to tumorigenesis and developmental disorders such as Down syndrome, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients. Overall design: To investigate changes in gene expression of RPE-1 cell lines upon siRNA-mediated knockdown of FAM53C, 48 hours post transfection.