2. Academic Validation
  3. SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity

SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity

  • Sci Adv. 2023 Jun 16;9(24):eade6624. doi: 10.1126/sciadv.ade6624.
Ming Tang 1,  Guofang Chen 1,  Bo Tu 2,  Zhiyi Hu 1,  Yujia Huang 1,  Christopher C DuFort 2,  Xiaoping Wan 1,  Zhiyong Mao 1,  Yongzhong Liu 3,  Wei-Guo Zhu 4,  Wen Lu 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 2 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
  • 4 Guangdong Key Laboratory of Genome Instability and Human Disease, Shenzhen University International Cancer Center, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China.
PMID: 37315132 DOI: 10.1126/sciadv.ade6624
Abstract

DNA damage repair (DDR) is a double-edged sword with different roles in Cancer susceptibility and drug resistance. Recent studies suggest that DDR inhibitors affect immune surveillance. However, this phenomenon is poorly understood. We report that methyltransferase SMYD2 plays an essential role in nonhomologous end joining repair (NHEJ), driving tumor cells adaptive to radiotherapy. Mechanically, in response to DNA damage, SMYD2 is mobilized onto chromatin and methylates Ku70 at lysine-74, lysine-516, and lysine-539, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Knockdown of SMYD2 or its inhibitor AZ505 results in persistent DNA damage and improper repair, which sequentially leads to accumulation of cytosolic DNA, and activation of cGAS-STING pathway and triggers antitumor immunity via infiltration and activation of cytotoxic CD8+ T cells. Our study reveals an unidentified role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting that SMYD2 is a promising therapeutic target for Cancer treatment.

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