Pyruvate kinase M2 phosphorylates H2AX and promotes genomic instability in human tumor cells

// Li Xia 1 , Kang Qin 1 , Xin-Ran Wang 1 , Xiao-Ling Wang 1 , Ai-Wu Zhou 1 , Guo-Qiang Chen 1 and Ying Lu 1 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China Correspondence to: Ying Lu, email: stove@shsmu.edu.cn Keywords: DNA damage; DNA damage response; pyruvate kinase; γ-H2AX; genomic instability Received: April 27, 2017      Accepted: October 28, 2017      Published: November 17, 2017 ABSTRACT Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP, a rate-limiting reaction in glycolysis. M2 isoform of PK (PKM2) is the predominant form of PK expressed in tumors. In addition to its well established cytosolic functions as a glycolytic enzyme, PKM2 displays nuclear localization and important nonmetabolic functions in tumorigenesis. Herein, we report that nuclear PKM2 interacts with histone H2AX under DNA damage conditions. Depletion of PKM2 decreased the level of serine 139-phosphorylated H2AX (γ-H2AX) in response to DNA damage. The in vitro kinase assay reveals that PKM2 directly phosphorylates H2AX at serine 139, which is abolished by the deletion of FBP-binding pocket of PKM2 (PKM2-Del 515-520 ). Replacement of wild type PKM2 with the kinase dead mutant PKM2-Del 515-520 leads to decreased cell proliferation and chromosomal aberrations under DNA damage conditions. Together, we propose that PKM2 promotes genomic instability in tumor cells which involves direct phosphorylation of H2AX. These findings reveal PKM2 as a novel modulator for genomic instability in tumor cells.