Arsenate‐mediated G2 cell cycle arrest in U‐2OS cells involves phosphorylation of human polycomb protein 2 by p38 MAPK

: G2/M checkpoints ensure the proper timing of cell mitosis. We previously reported that p38 mitogen-activated protein kinase (MAPK) activation is essential for stress-induced G2 arrest in the U-2OS osteosarcoma cell line, but the molecular mechanism was obscure. Here, using the T7 phage display system, we find p38 directly binds to human polycomb protein 2 (HPC2), and arsenate-induced G2 arrest in U-2OS cell is p38- and phosphorylation of HPC2-dependent. Phosphorylation of HPC2 at threonine 495 is required for recruiting Ring1 and Rb family proteins to form the polycomb repressive complex (PRC), and PRC is required for arsenate-induced downregulation of CDC2 expression. Thus, p38 MAPK regulates cell cycle progression through phosphorylation of HPC2 to mediate transcriptional repression, providing a mechanistic link for arsenate-induced transcriptional silencing.