H2B monoubiquitination is a key epigenetic regulator of ferroptosis and is regulated by p53 (2019)
Figure 7

Figure 7. Effects of the p53-USP7-H2Bub1 axis on ferroptosis.

A, H1299 cells transfected with a Flag-tagged p53 or an empty plasmid together with a USP7-specific siRNA or a control siRNA (siCont.) as were treated with 12 μM erastin (+) or untreated (-) for 24 h as indicated. Representative phase-contrast images were recorded (magnification, ×20), and the surviving cells were counted.

B, H1299 cells treated as in (A) were subjected to transmission electron microscopy. Representative images are shown. Arrow head indicates condensed and marginated chromatin.

C, Lipid ROS levels were examined in cells treated as in (A and B).

D, Working model. Normal cells or cells without p53 show relatively low levels of nuclear USP7. H2Bub1 is maintained at relatively high levels and is required for normal SLC7A11 expression. However, when cells are subjected to ferroptotic stress (e.g., erastin treatment), increasing amounts of p53 interact with USP7 and promote the nuclear translocation of USP7. The translocated USP7 further removes H2Bub1 from the SLC7A11 gene regulatory region and inactivates SCL7A11 expression. Eventually, ferroptosis occurs.

Data information: Bars and error bars are mean±s.d., n=3 independent repeats. Two-tailed unpaired Student's t-test was performed. *: p<0.05.

Disclosure of Potential Conflicts of Interest

The authors declare that no potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. Yan Zhang from the Institut Pasteur of Shanghai, Chinese Academy of Sciences, for kindly providing the USP7-related plasmids, and Dr. Zhi-Xiong Xiao from Sichuan University for kindly providing the "gain-of-function" mutants of p53.

This work was supported by the National Natural Science Foundation of China (Grant No. 81773009), the Fundamental Research Funds for the Central Universities (Xi'an Jiao Tong University, Grant No. 2017qngz13), and the China Postdoctoral Science Foundation (Grant Nos. 2017M613149 and 2018T111038).

Author contributions

S.C. designed the study; Y.F.W., L.Y., X.J.Z., W.C., Y.P.L., Q.R.S., Q.H., S.Y.Z., G.A.Z., and Y.Q.W. performed the experiments; S.C., Y.F.W., and L.Y. analyzed the data; S.C. wrote the manuscript.

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