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Review
. 2013 Jul;29(7):394-402.
doi: 10.1016/j.tig.2013.02.003. Epub 2013 Mar 26.

WEE1 tyrosine kinase, a novel epigenetic modifier

Kiran Mahajan  1 , Nupam P Mahajan
Affiliations
Review

WEE1 tyrosine kinase, a novel epigenetic modifier

Kiran Mahajan et al. Trends Genet. 2013 Jul.

Abstract

The cell cycle requires cells to duplicate their chromatin, DNA, and histones, while retaining a subset of epigenetic marks, in a highly coordinated manner. The WEE1 kinase was identified as an important regulator during S phase, preventing entry into mitosis until DNA replication has been completed. Interestingly, WEE1 has also emerged as a key player in regulating histone synthesis. It phosphorylates histone H2B at tyrosine 37 in the nucleosomes found upstream of the histone gene cluster, and this suppresses histone transcription in late S phase. These observations highlight a dual role for WEE1 as both a mitotic gatekeeper and a surveyor of chromatin synthesis, providing a direct link between epigenetics and cell-cycle progression. Importantly, this link has implications for the design of novel epigenetic inhibitors targeting cancers that display elevated expression of this kinase.

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Figures

Figure 1
Figure 1. Schematic outlining WEE1 functions
WEE1 is emerging as a critical surveyor of chromatin integrity across the evolutionary landscape by regulating histone synthesis and the cell cycle. It controls genome stability by regulating the activity of factors such as CDKs involved in replication initiation during S phase. During DNA replication, it negatively regulates the activity of the Mus81 endonuclease at stalled replication forks to prevent formation of DNA double strand breaks and preserve genetic integrity. Importantly, it appears to couple DNA synthesis with histone synthesis due to its ability to prevent mitotic entry until DNA synthesis is completed and to switch off histone transcription, by modifying core histone H2B, at the end of S phase. These functions are likely to be critical for its ability to delay chromosome condensation and prevent aneuploidy.
Figure 2
Figure 2. A model for WEE1 in chromatin integrity during replication stress
Replication protein A (RPA) (small magenta circles) coats ssDNA formed during DNA replication and DNA repair which facilitates the localization of Ataxia-Telangiectasia mutated and RAD3-related (ATR) kinase to sites of DNA damage in both human and yeast systems. Activated ATR phosphorylates the downstream checkpoint kinase-1 (CHK1) which in turn phosphorylates and activates WEE1. In addition to WEE1 activation, CHK1 also phosphorylates and inactivates CDC25, a phosphatase that dephosphorylates CDK1. WEE1 plays a crucial role in maintaining chromatin integrity during DNA damage or replication stress by performing 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 in nucleosomes upstream of histone cluster 1 (Hist1). H2B Tyr37 phosphorylation prevents binding of the transcriptional coactivator NPAT and RNA polymerase II and recruits the histone chaperone HIRA upstream of the Hist1 cluster thereby avoiding overproduction of histones. 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.
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