Theranostics 2023; 13(3):973-990. doi:10.7150/thno.79688 This issue Cite

Research Paper

Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer

Fang-Lin Zhang1,2,3,#, Shao-Ying Yang1,2,3,#, Li Liao1,2,3,#, Tai-Mei Zhang1, Yin-Ling Zhang1,2,3, Shu-Yuan Hu1, Ling Deng1, Min-Ying Huang1, Lisa Andriani4, Xiao-Yan Ma4, Zhi-Min Shao1,2,3,4,5,6✉, Da-Qiang Li1,2,3,4,5,6✉

1. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
2. Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China
3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
4. Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai 200032, China
5. Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai 200032, China
6. Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, China
# These authors contributed equally to this work.

Citation:
Zhang FL, Yang SY, Liao L, Zhang TM, Zhang YL, Hu SY, Deng L, Huang MY, Andriani L, Ma XY, Shao ZM, Li DQ. Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer. Theranostics 2023; 13(3):973-990. doi:10.7150/thno.79688. https://www.thno.org/v13p0973.htm
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Abstract

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Rationale: SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic.

Methods: In vivo and in vitro SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through in vitro and in vivo functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms.

Results: Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs.

Conclusions: Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.

Keywords: Breast cancer, MORC2, SUMOylation, DNA damage response, Therapeutic resistance


Citation styles

APA
Zhang, F.L., Yang, S.Y., Liao, L., Zhang, T.M., Zhang, Y.L., Hu, S.Y., Deng, L., Huang, M.Y., Andriani, L., Ma, X.Y., Shao, Z.M., Li, D.Q. (2023). Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer. Theranostics, 13(3), 973-990. https://doi.org/10.7150/thno.79688.

ACS
Zhang, F.L.; Yang, S.Y.; Liao, L.; Zhang, T.M.; Zhang, Y.L.; Hu, S.Y.; Deng, L.; Huang, M.Y.; Andriani, L.; Ma, X.Y.; Shao, Z.M.; Li, D.Q. Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer. Theranostics 2023, 13 (3), 973-990. DOI: 10.7150/thno.79688.

NLM
Zhang FL, Yang SY, Liao L, Zhang TM, Zhang YL, Hu SY, Deng L, Huang MY, Andriani L, Ma XY, Shao ZM, Li DQ. Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer. Theranostics 2023; 13(3):973-990. doi:10.7150/thno.79688. https://www.thno.org/v13p0973.htm

CSE
Zhang FL, Yang SY, Liao L, Zhang TM, Zhang YL, Hu SY, Deng L, Huang MY, Andriani L, Ma XY, Shao ZM, Li DQ. 2023. Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer. Theranostics. 13(3):973-990.

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