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SCML2 contributes to tumor cell resistance to DNA damage through regulating p53 and CHK1 stability

Cell Death & Differentiation volume 30, pages 1849–1867 (2023)Cite this article

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Abstract

SCML2 has been found to be highly expressed in various tumors. However, the extent to which SCML2 is involved in tumorigenesis and cancer therapy is yet to be fully understood. In this study, we aimed to investigate the relationship between SCML2 and DNA damage response (DDR). Firstly, DNA damage stabilizes SCML2 through CHK1-mediated phosphorylation at Ser570. Functionally, this increased stability of SCML2 enhances resistance to DNA damage agents in p53-positive, p53-mutant, and p53-negative cells. Notably, SCML2 promotes chemoresistance through distinct mechanisms in p53-positive and p53-negative cancer cells. SCML2 binds to the TRAF domain of USP7, and Ser441 is a critical residue for their interaction. In p53-positive cancer cells, SCML2 competes with p53 for USP7 binding and destabilizes p53, which prevents DNA damage-induced p53 overactivation and increases chemoresistance. In p53-mutant or p53-negative cancer cells, SCML2 promotes CHK1 and p21 stability by inhibiting their ubiquitination, thereby enhancing the resistance to DNA damage agents. Interestingly, we found that SCML2A primarily stabilizes CHK1, while SCML2B regulates the stability of p21. Therefore, we have identified SCML2 as a novel regulator of chemotherapy resistance and uncovered a positive feedback loop between SCML2 and CHK1 after DNA damage, which serves to promote the chemoresistance to DNA damage agents.

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Fig. 1: SCML2 depletion led to decreased cell survival after DNA damage.
Fig. 2: CHK1 stabilized SCML2 after DNA damage through phosphorylation.
Fig. 3: Ser 441 of SCML2 is the key residue for its interaction with USP7.
Fig. 4: SCML2 prevents p53 overactivation after DNA damage.
Fig. 5: SCML2 prevents DNA damage induced cell death in p53 positive cells.
Fig. 6: SCML2 stabilizes p21 through USP7 mediated deubiquitination.
Fig. 7: SCML2 regulates the stability of CHK1.
Fig. 8: SCML2 is upregulated in p53 negative chemoresistant cancer cells.

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Data availability

All the uncropped original western blots used in the manuscript were listed in Original Western blot images file in Supplementary materials.

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Funding

QC is supported by grants from the National Key Research and Development Program of China (2018YFC1003400), the National Natural Science Foundation of China (32170698, 31770868) and the Fundamental Research Funds for the Central Universities (2042022dx0003).

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Author notes

  1. These authors contributed equally: Qianqian Peng, Xin Shi.

Authors and Affiliations

  1. Department of Radiation and Medical Oncology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, PR China

    Qianqian Peng, Xin Shi, Dingwei Li, Jing Guo, Xiaqing Zhang & Qiang Chen

  2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, PR China

    Qianqian Peng, Xin Shi, Dingwei Li, Jing Guo, Xiaqing Zhang & Qiang Chen

  3. College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, PR China

    Xiaoyan Zhang

  4. College of Life Science and Technology, Huazhong Agricultural University, Wuhan, PR China

    Xiaoyan Zhang

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  1. Qianqian Peng
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Contributions

QC designed and supervised the study. Q-QP studied the regulation between SCML2 and CHK1. XS constructed all the cell lines and analyzed the regulation between SCML2, USP7 and p21. Q-QP and XS jointly performed the remaining experiments. D-WL performed MST assay. JG and X-QZ generated constructs and purified proteins. QC, XS, X-YZ and Q-QP wrote the manuscript.

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Correspondence to Qiang Chen.

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Peng, Q., Shi, X., Li, D. et al. SCML2 contributes to tumor cell resistance to DNA damage through regulating p53 and CHK1 stability. Cell Death Differ 30, 1849–1867 (2023). https://doi.org/10.1038/s41418-023-01184-3

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