Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China.
Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing, 100191, China.
Oncogene. 2022 Jul;41(29):3694-3704. doi: 10.1038/s41388-022-02383-x. Epub 2022 Jun 22.
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.
尤文肉瘤断点区域 1（EWSR1）是 FET（FUS/EWSR1/TAF15）RNA 结合蛋白家族的成员。尤文肉瘤癌蛋白 EWS-FLI1 已经得到了广泛的研究，而对 EWSR1 本身的了解要少得多，特别是 EWSR1 在应对 DNA 损伤方面的潜在作用。在这里，我们发现紫外线照射诱导 EWSR1 的乙酰化，这对于其核仁易位是必需的。我们确定 K423、K432、K438、K640 和 K643 是主要的乙酰化位点，p300/CBP 和 HDAC3/HDAC10 分别是主要的乙酰转移酶和去乙酰化酶。从机制上讲，紫外线诱导的 EWSR1 乙酰化抑制了其与剪接体成分 U1C 的相互作用，导致 CHK2 的异常剪接，从而抑制 CHK2 在紫外线照射下的活性。总之，我们的研究结果揭示了乙酰化是 EWSR1 的一种新型调节修饰，对于其在 DNA 损伤反应中的功能至关重要。
