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Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage

Abstract

Ewing sarcoma breakpoint region 1 (EWSR1) is a member of FET (FUS/EWSR1/TAF15) RNA-binding family of proteins. The Ewing sarcoma oncoprotein EWS-FLI1 has been extensively studied, while much less is known about EWSR1 itself, especially the potential role of EWSR1 in response to DNA damage. Here, we found that UV irradiation induces acetylation of EWSR1, which is required for its nucleoli translocation. We identified K423, K432, K438, K640, and K643 as the major acetylation sites, p300/CBP and HDAC3/HDAC10 as the major acetyltransferases and deacetylases, respectively. Mechanically, UV-induced EWSR1 acetylation repressed its interaction with spliceosomal component U1C, which caused abnormal splicing of CHK2, suppressing the activity of CHK2 in response to UV irradiation. Taken together, our findings uncover acetylation as a novel regulatory modification of EWSR1, and is essential for its function in DNA damage response.

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Fig. 1: EWSR1 acetylation promotes its nucleolus translocation upon UV irradiation.
Fig. 2: EWSR1 is mainly acetylated by acetyltransferase p300.
Fig. 3: HDAC3 deacetylates EWSR1.
Fig. 4: EWSR1 is acetylated at many sites by p300.
Fig. 5: Hyperacetylated EWSR1 regulates alternative splicing-mediated CHK2 expression to repress cell growth.
Fig. 6: Reduced CHK2 in hyperacetylated EWSR1 cells is mediated by spliceosomal factor U1C.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (81874147, 82172959). We thank core facility at Peking University Health Science Center for experiment help.

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TZ and JL designed the research; TZ, ZW, ML, LL, XY, YZ, JB, and YL performed the experiments; TZ, ZW, MR, CS, and WW analyzed data; TZ, HT, JL drafted the manuscript; TZ and JL modified the manuscript.

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Correspondence to Hongyu Tan or Jianyuan Luo.

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Zhang, T., Wang, Z., Liu, M. et al. Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage. Oncogene 41, 3694–3704 (2022). https://doi.org/10.1038/s41388-022-02383-x

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