H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes

Histone gene transcription is downregulated after DNA synthesis is completed, but how cells terminate histone gene transcription has been unknown. A new study uncovers that phosphorylation of histone H2B at Tyr37 by WEE1 kinase leads to a coordinated transcriptional repression of replication-dependent core histone genes in the late S/G2 phase in yeast and mammalian cells. Histone gene transcription is actively downregulated after completion of DNA synthesis to avoid overproduction. However, the precise mechanistic details of the cessation of histone mRNA synthesis are not clear. We found that histone H2B phosphorylation at Tyr37 occurs upstream of histone cluster 1, Hist1 , during the late S phase. We identified WEE1 as the kinase that phosphorylates H2B at Tyr37. Loss of expression or inhibition of WEE1 kinase abrogated H2B Tyr37 phosphorylation with a concomitant increase in histone transcription in yeast and mammalian cells. H2B Tyr37 phosphorylation excluded binding of the transcriptional coactivator NPAT and RNA polymerase II and recruited the histone chaperone HIRA upstream of the Hist1 cluster. Taken together, our data show a previously unknown and evolutionarily conserved function for WEE1 kinase as an epigenetic modulator that marks chromatin with H2B Tyr37 phosphorylation, thereby inhibiting the transcription of multiple histone genes to lower the burden on the histone mRNA turnover machinery.