UC San Diego

In eukaryotes, genomic DNA is packaged into histone proteins, which can undergo post-translational modifications that are in turn critical in regulating transcription, the cell cycle, DNA replication, and DNA damage repair. In this study, we identify a novel tyrosine phosphorylation in histone H2A (Y57) that is conserved from yeast to mammals. Surprisingly, the phosphorylation is mediated by an unsuspected tyrosine kinase activity of casein kinase 2 (CK2). Mutation of the Y57 residue or inhibition of CK2 activity impairs transcriptional elongation, marked by a decrease in the recruitment of RNA polymerase II across active genes in yeast as well as mammalian cells. Genome-wide binding analysis reveals that CK2 alpha, the catalytic subunit of CK2, binds across RNA polymerase II-transcribed coding genes and active enhancers. Mutation of Y57 causes a defect in transcriptional elongation and DNA damage repair. At the molecular level, Y57 mutation causes a dramatic loss of H2B mono-ubiquitylation as well as H3K4me3 and H3K79me3 (histone marks associated with active transcription), a decrease in H2A mono-ubiquitylation and an increase in H2A S128 (H2AX S139 in mammals) phosphorylation (histone mark associated with DNA damage). Mechanistically, both CK2 inhibition and H2A-Y57F mutation antagonize the H2B deubiquitylation activity of the SAGA complex, suggesting a critical role of this novel phosphorylation event in coordinating the activity of the SAGA complex during transcription and DNA damage repair. Together, these results identify a new component of regulation in transcriptional elongation and DNA damage repair based on CK2-dependent tyrosine phosphorylation of the globular domain of H2A