WEE1-H2B SIGNALING

A Novel Epigenetic Function of WEE1

We discovered that WEE1 kinase phosphorylates histone H2B at Tyr37 (py37-H2B) in a window of 30-40 minutes in late S phase. Eukaryotic cells precisely regulates histone levels by shutting off histone transcription at the end of DNA synthesis. WEE1 kinase deposit pY37-H2B epigenetic marks upstream of Hist1 cluster, suppressing global histone transcription in both yeast and mammalian cells.

Our data provides crucial evidence that in addition to mRNA turnover, histone transcription shut off would efficiently lower histone transcript levels once DNA synthesis is complete, eliminating overproduction of core histones. Thus, WEE1, a cell cycle regulator has a dual role as an epigenetic modifier that maintains histone transcript levels.

  • Mahajan K, Fang B, Koomen JM and Mahajan NP*. H2B Tyr37 phosphorylation suppresses expression of replication-dependent core histone genes. Nature Structural & Molecular Biology 2012

WEE1 epigenetically regulates 5hmC levels

WEE1 kinase has been reported to be aberrantly expressed in melanomas, glioblastoma multiforme (GBMs), triple negative breast cancers (TNBCs) and prostate cancer. Dependence of various cancer cells on WEE1 signaling suggests that targeting epigenetic activity of WEE1 is a viable strategy.

Clinical significance of WEE1 epigenetic signaling in Melanoma and GBM

WEE1-H2B epigenetic signaling plays a crucial role in various malignancies such as melanoma, GBM and prostate cancer

WEE1 phosphorylates H2B at Tyr37 upstream of histone cluster 1, Hist1. NPAT is excluded from binding to the Hist1 cluster because of its inability to recognize pY37-H2B, which in turn inhibits RNA polymerase II (Pol II) recruitment. Subsequently, HIRA is recruited to pY37-H2B, preventing NPAT rebinding and suppressing histone mRNA synthesis.
WEE1 in chromatin integrity during replication stress. Replication protein A (RPA) coats ssDNA formed during DNA replication and DNA repair, which facilitates the localization of ATR kinase to sites of DNA damage. ATR phosphorylates the CHK1 which in turn phosphorylates and activates WEE1. WEE1 perform two distinct phosphorylations; first, it phosphorylates CDK1 at Y15 preventing entry into mitosis so as to allow repair of damaged DNA. Second, it actively downregulates histone gene transcription by marking H2B at Tyr37. The collective outcome of these events is initiation of intra-S phase and G2 checkpoints in response to DNA damage or replication stress and maintenance of chromatin integrity during repair of damaged DNA, prior to entry into mitosis.