SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair by Ming Tang, Zhiming Li, Chaohua Zhang, Xiaopeng Lu, Bo Tu, Ziyang.

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SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair by Ming Tang, Zhiming Li, Chaohua Zhang, Xiaopeng Lu, Bo Tu, Ziyang Cao, Yinglu Li, Yongcan Chen, Lu Jiang, Hui Wang, Lina Wang, Jiadong Wang, Baohua Liu, Xingzhi Xu, Haiying Wang, and Wei-Guo Zhu Science Volume 5(3):eaav1118 March 27, 2019 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 1 SIRT7 deficiency results in persistent ATM acetylation. SIRT7 deficiency results in persistent ATM acetylation. (A) HCT116 cells were irradiated at 10 Gy and released for the indicated time periods. Cell lysates were subjected to immunoprecipitation (IP) analysis. Pan-ac antibody, Pan-acetyl-lysine antibody. (B) HCT116 cells were treated with or without NAM at 10 mM or TSA at 1 μM and irradiated at 10 Gy and released for 8 hours. Cell lysates were subjected to IP analysis. (C) HCT116 cells were transfected with the indicated siRNAs and radiated at 10 Gy and released for 8 hours. Cell lysates were subjected to IP analysis. (D) HCT116 cells were transfected with the indicated siRNAs and radiated at 10 Gy and released for the indicated time periods. Cell lysates were subjected to IP analysis. (E) HCT116 cells were transfected with the indicated siRNAs and irradiated at 5, 10, or 20 Gy and released for 8 hours. Cell lysates were subjected to IP analysis. (F) HCT116 cells were transfected with the indicated siRNAs or plasmids and irradiated at 10 Gy and released for 8 hours. Cell lysates were subjected to IP analysis. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 2 SIRT7 interacts with ATM and regulates ATM activity. SIRT7 interacts with ATM and regulates ATM activity. (A and B) Chromatin proteins were immunoprecipitated with an anti-ATM antibody or anti-SIRT7 antibody for IP analysis. IgG, immunoglobulin G. (C) HCT116 cells were treated with IR at 10 Gy and released for the indicated time periods. Chromatin proteins were subjected to IP analysis. (D) HCT116 cells were treated with IR at 10 Gy and released for the indicated time periods. Chromatin proteins were subjected to immunoblotting analysis. (E) GST alone, FL GST-SIRT7, an N-terminal fragment (1 to 89 aa), a deacetylase core fragment (90 to 331 aa), or a C-terminal fragment (332 to 400 aa) were incubated with HCT116 cell lysates for the GST pulldown assay. CBB, Coomassie brilliant blue. “*” represents specific protein bands. (F) GST alone or GST-tagged ATM fragments were incubated with HCT116 cell lysates with overexpressed FLAG-SIRT7 for the GST pulldown assay. CBB: Coomassie brilliant blue “*” represents specific protein bands. (G) HCT116 cells were transfected with the indicated siRNAs or plasmids and irradiated at 10 Gy and released for 8 hours. Cell extracts were subjected to IP analysis. (H and I) Fragment (2712 to 3056 aa) or FL FLAG-ATM proteins were purified from irradiated cells (10 Gy, 1 hour post-IR) and incubated with purified WT or mutant (H187Y) FLAG-SIRT7 with or without NAD+. The acetylation levels were determined by immunoblotting using an anti–pan-lysine-acetylation antibody or anti–ATM-acK3016 antibody. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 3 SIRT7 affects ATM autophosphorylation and dimer dissociation. SIRT7 affects ATM autophosphorylation and dimer dissociation. (A) HCT116 cells were transfected with the indicated siRNAs and irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were analyzed by immunoblotting. (B) HCT116 cells were transfected with the indicated siRNAs or plasmids and irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were analyzed by immunoblotting. (C and D) HCT116 cells were transfected with the indicated plasmids or siRNAs and irradiated at 10 Gy and released for the indicated time periods. Whole-cell extracts were subjected to Co-IP analysis. (E) ATM stable knockdown HCT116 cells were transfected with the indicated plasmids and irradiated at 10 Gy and released for the indicated time periods. Whole-cell extracts were subjected to Co-IP analysis. (F) HCT116 cells were transfected with the indicated plasmids and irradiated at 10 Gy and released for 1 hour. Whole-cell extracts were subjected to Co-IP analysis. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 4 SIRT7 is required for DNA damage repair. SIRT7 is required for DNA damage repair. (A) HCT116 cells were transfected with the indicated siRNAs and irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were subjected to immunoblotting analysis. (B) WT or SIRT7 KO (1# and 2#) cells were subjected to colony formation assay. All data represent the means ± SD. (C) WT or SIRT7 KO (1#) cells were subjected to comet assay. The original representative images were shown on the left panel. All data represent the means ± SD. (D and E) DR-U2OS and pEJ5-U2OS cells were transfected with the indicated plasmids or siRNAs and subjected to HR and NHEJ assays, respectively. All data represent the means ± SD. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 5 SIRT7-mediated ATM deacetylation is required for DNA damage repair and cell survival. SIRT7-mediated ATM deacetylation is required for DNA damage repair and cell survival. (A) HCT116 cells were transfected with the indicated siRNAs and treated with or without Ku55933 at 10 μM for 12 hours. Cells were irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were subjected to immunoblotting. (B) WT or SIRT7 KO (1#) cells were treated with Ku55933 at 10 μM for 12 hours and then subjected to comet assay. All data represent the means ± SD. (C) ATM stable knockdown (shATM) or control (shCtr) HCT116 cells were treated with Ku55933 at 10 μM for 12 hours. Cells were irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were subjected to immunoblotting. (D) ATM stable knockdown WT or SIRT7 KO cells were subjected to comet assay. All data represent the means ± SD. (E) ATM stable knockdown or control cells were transfected with the indicated plasmids and irradiated at 10 Gy and released for the indicated time periods. Total cell lysates were subjected to immunoblotting. (F) ATM stable knockdown cells were transfected with the indicated plasmids and subjected to comet assay. The bottom panel shows immunoblotting of total cell lysates. All data represent the means ± SD. (G and H) ATM stable knockdown DR-U2OS and pEJ5-U2OS cells transfected with the indicated plasmids and subjected to HR and NHEJ assays, respectively. The bottom panels show immunoblotting of total cell lysates. All data represent the means ± SD. (I) Control knockdown (shCtr), ATM stable knockdown (shATM), or ATM stable knockdown with reintroduction of vector, WT ATM, or K3016Q mutant ATM cells was subjected to colony formation assay. All data represent the means ± SD. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Fig. 6 Schematic model of SIRT7-mediated ATM deacetylation in DNA damage repair. Schematic model of SIRT7-mediated ATM deacetylation in DNA damage repair. In response to DNA damage, ATM is sequentially modified by TIP60-mediated acetylation and autophosphorylation, which dictates ATM activation in coordination with the MRN complex. At late stages of DNA damage repair, SIRT7 is gradually recruited to DNA damage sites and deacetylates ATM, which is required for its dephosphorylation by phosphatase WIP1. ATM is then dimerized into inactive form. Thus, TIP60- and SIRT7-dependent balance of ATM acetylation controls its activity in response to DNA damage. Ming Tang et al. Sci Adv 2019;5:eaav1118 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).