Acetylation of MORC2 by NAT10 Regulates Cell-cycle Checkpoint Control and Resistance to DNA-damaging Chemotherapy and Radiotherapy in Breast Cancer

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2020 Mar 1

PMID 32112098

Citations 93

Authors

Hong-Yi Liu

Ying-Ying Liu

Fan Yang

Lin Zhang

Fang-Lin Zhang

Xin Hu

Zhi-Min Shao

Da-Qiang Li

Affiliations

Soon will be listed here.

Abstract

MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.

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References

Wang L, Du Y, Lu M, Li T . ASEB: a web server for KAT-specific acetylation site prediction. Nucleic Acids Res. 2012; 40(Web Server issue):W376-9. PMC: 3394258. DOI: 10.1093/nar/gks437. View

Li F, Liu J, Bao R, Yan G, Feng X, Xu Y . Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. Nat Commun. 2018; 9(1):508. PMC: 5802808. DOI: 10.1038/s41467-018-02950-5. View

Ando M, Okamoto Y, Yoshimura A, Yuan J, Hiramatsu Y, Higuchi Y . Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan. Eur J Neurol. 2017; 24(10):1274-1282. DOI: 10.1111/ene.13360. View

Yan Y, Hein A, Greer P, Wang Z, Kolb R, Batra S . A novel function of HER2/Neu in the activation of G2/M checkpoint in response to γ-irradiation. Oncogene. 2014; 34(17):2215-26. PMC: 4362969. DOI: 10.1038/onc.2014.167. View

Liu X, Cai S, Zhang C, Liu Z, Luo J, Xing B . Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress. Nucleic Acids Res. 2018; 46(18):9601-9616. PMC: 6182161. DOI: 10.1093/nar/gky777. View

Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S . Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun. 2017; 8(1):1823. PMC: 5703960. DOI: 10.1038/s41467-017-01947-w. View

Choudhary C, Weinert B, Nishida Y, Verdin E, Mann M . The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014; 15(8):536-50. DOI: 10.1038/nrm3841. View

Balmus G, Larrieu D, Barros A, Collins C, Abrudan M, Demir M . Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nat Commun. 2018; 9(1):1700. PMC: 5923383. DOI: 10.1038/s41467-018-03770-3. View

Iyer L, Abhiman S, Aravind L . MutL homologs in restriction-modification systems and the origin of eukaryotic MORC ATPases. Biol Direct. 2008; 3:8. PMC: 2292703. DOI: 10.1186/1745-6150-3-8. View

10.

Ashwell S, Zabludoff S . DNA damage detection and repair pathways--recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res. 2008; 14(13):4032-7. DOI: 10.1158/1078-0432.CCR-07-5138. View

11.

Elia A, Boardman A, Wang D, Huttlin E, Everley R, Dephoure N . Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response. Mol Cell. 2015; 59(5):867-81. PMC: 4560960. DOI: 10.1016/j.molcel.2015.05.006. View

12.

Sanchez-Solana B, Li D, Kumar R . Cytosolic functions of MORC2 in lipogenesis and adipogenesis. Biochim Biophys Acta. 2013; 1843(2):316-26. PMC: 3923981. DOI: 10.1016/j.bbamcr.2013.11.012. View

13.

Douse C, Bloor S, Liu Y, Shamin M, Tchasovnikarova I, Timms R . Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms. Nat Commun. 2018; 9(1):651. PMC: 5811534. DOI: 10.1038/s41467-018-03045-x. View

14.

Zhang L, Li D . MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res. 2019; 47(16):8502-8520. PMC: 6895267. DOI: 10.1093/nar/gkz545. View

15.

Beli P, Lukashchuk N, Wagner S, Weinert B, Olsen J, Baskcomb L . Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. Mol Cell. 2012; 46(2):212-25. PMC: 3565437. DOI: 10.1016/j.molcel.2012.01.026. View

16.

Pan Z, Ding Q, Guo Q, Guo Y, Wu L, Wu L . MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance. Int J Oncol. 2018; 53(1):59-72. PMC: 5958890. DOI: 10.3892/ijo.2018.4333. View

17.

Hornbeck P, Zhang B, Murray B, Kornhauser J, Latham V, Skrzypek E . PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2014; 43(Database issue):D512-20. PMC: 4383998. DOI: 10.1093/nar/gku1267. View

18.

Wu J, Zhu H, Wu J, Chen W, Guan X . Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer. Am J Transl Res. 2018; 10(1):256-264. PMC: 5801363. View

19.

Castedo M, Perfettini J, Roumier T, Andreau K, Medema R, Kroemer G . Cell death by mitotic catastrophe: a molecular definition. Oncogene. 2004; 23(16):2825-37. DOI: 10.1038/sj.onc.1207528. View

20.

Sancho P, Bartesaghi L, Miossec O, Garcia-Garcia F, Ramirez-Jimenez L, Siddell A . Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations. Hum Mol Genet. 2019; 28(10):1629-1644. DOI: 10.1093/hmg/ddz006. View