Mysm1-KO Mouse

MYSM1, a metalloprotease family protein, has deubiquitinase catalytic activity along with SANT and SWIRM domains. It is a crucial regulator in the hematopoietic system, influencing stem cell function, blood cell production, and immune response. MYSM1 localizes to the nucleus, where it regulates gene expression by deubiquitinating histone H2A and interacting with other transcriptional regulators. A cytosolic form also exists, regulating innate immunity signal transduction pathways [1].

MYSM1 knockout mice exhibit developmental abnormalities across multiple tissues. In neural stem cells (NSCs), Mysm1 knockdown in mice leads to abnormal brain development, microcephaly, and altered NSC proliferation and differentiation. Mysm1 epigenetically regulates Id4 transcription, and rescuing Id4 expression reverses the abnormal phenotypes of Mysm1-deficient NSCs [4]. In the heart, cardiomyocyte-specific knockdown of MYSM1 protects against doxorubicin-induced cardiotoxicity and cardiac hypertrophy, indicating its role in cardiac pathophysiology [3,5]. In breast cancer, MYSM1 expression is decreased, especially in triple-negative breast cancer (TNBC), and its overexpression induces apoptosis and sensitizes TNBC cells to cisplatin [2].

In conclusion, MYSM1 plays essential roles in various biological processes, including tissue development, stem cell function, and immune response. Studies using MYSM1 knockout or knockdown mouse models have revealed its significance in diseases such as hematopoietic disorders, neural development abnormalities, cardiac diseases, and cancer. These models provide valuable insights into the etiology of MYSM1-related human disorders and suggest MYSM1 as a potential therapeutic target.

References:

1. Fiore, Amanda, Liang, Yue, Lin, Yun Hsiao, Langlais, David, Nijnik, Anastasia. 2020. Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review. In International journal of molecular sciences, 21, . doi:10.3390/ijms21083007. https://pubmed.ncbi.nlm.nih.gov/32344625/

2. Guan, Xiaolin, Meng, Xin, Zhu, Keyu, Lu, Renquan, Guo, Lin. 2022. MYSM1 induces apoptosis and sensitizes TNBC cells to cisplatin via RSK3-phospho-BAD pathway. In Cell death discovery, 8, 84. doi:10.1038/s41420-022-00881-1. https://pubmed.ncbi.nlm.nih.gov/35217648/

3. Shi, Xiaowen, Xu, Jianjiang, Zhong, Xin, Zheng, Zhanxiong, Han, Jibo. 2024. Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes. In Cell communication and signaling : CCS, 22, 593. doi:10.1186/s12964-024-01955-6. https://pubmed.ncbi.nlm.nih.gov/39695708/

4. Xu, Zhenhua, Qin, Qiaozhen, Wang, Yan, Xu, Donggang, Jiang, Xiaoxia. 2024. Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression. In Cell death & disease, 15, 129. doi:10.1038/s41419-024-06530-y. https://pubmed.ncbi.nlm.nih.gov/38342917/

5. Zhong, Xin, Xu, Jianjiang, Shi, Xiaowen, Xu, Jiajun, Han, Jibo. 2025. MYSM1 Mediates Cardiac Parthanatos and Hypertrophy by Deubiquitinating PARP1. In Hypertension (Dallas, Tex. : 1979), 82, 704-715. doi:10.1161/HYPERTENSIONAHA.124.23823. https://pubmed.ncbi.nlm.nih.gov/39907013/