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<p>Posttranslational modification succinylation plays a pivotal role in tumorigenesis across malignancies, yet its mechanistic contributions to hepatocellular carcinoma (HCC) pathogenesis and therapeutic resistance remain poorly characterized. In this study, we systematically demonstrated that the splicing factor SRSF11 undergoes functional consequential succinylation in HCC progression. Mechanistically, lysine acetyltransferase 2 A (KAT2A) directly interacts with SRSF11 to catalyze its succinylation at lysine 419 (K419), thereby enhancing DNA damage repair capacity in both in vitro and in vivo HCC models. Structural and functional analyses revealed that K419 succinylation stabilizes SRSF11-spliceosome interactions, which promote the inclusion of exon 10 of RAD52 through enhanced pre-mRNAs binding. This exon-specific splicing event preserves the RAD51-binding domain essential for homologous recombination (HR) repair, ultimately facilitating RAD52-RAD51 dimer assembly and HR-mediated genomic stabilization. Clinically, elevated SRSF11 expression is correlated with increased HR activity, radioresistance, and reduced survival in HCC patients. Notably, genetic disruption of the KAT2A-SRSF11 axis sensitizes HCC cells to radiation-induced apoptosis. Our findings establish succinylation as a novel regulatory mechanism linking alternative splicing to DNA repair fidelity in HCC, while proposing therapeutic targeting of this pathway to overcome radioresistance in advanced HCC.</p>

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KAT2A-driven succinylation of SRSF11 enforces spliceosome-mediated RAD52 splicing to promote homologous recombination and radioresistance in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Jun Wu,
  • Jingsheng Yuan,
  • Zijian Liu,
  • Yongjie Zhou,
  • Bo Zhang,
  • Yahong Xu,
  • Qiwen Zeng,
  • Zhenru Wu,
  • Lingxiang Kong,
  • Jiaguo Wang,
  • Bohan Zhang,
  • Jian Yang,
  • Tao Lv,
  • Yujun Shi,
  • Jiayin Yang

摘要

Posttranslational modification succinylation plays a pivotal role in tumorigenesis across malignancies, yet its mechanistic contributions to hepatocellular carcinoma (HCC) pathogenesis and therapeutic resistance remain poorly characterized. In this study, we systematically demonstrated that the splicing factor SRSF11 undergoes functional consequential succinylation in HCC progression. Mechanistically, lysine acetyltransferase 2 A (KAT2A) directly interacts with SRSF11 to catalyze its succinylation at lysine 419 (K419), thereby enhancing DNA damage repair capacity in both in vitro and in vivo HCC models. Structural and functional analyses revealed that K419 succinylation stabilizes SRSF11-spliceosome interactions, which promote the inclusion of exon 10 of RAD52 through enhanced pre-mRNAs binding. This exon-specific splicing event preserves the RAD51-binding domain essential for homologous recombination (HR) repair, ultimately facilitating RAD52-RAD51 dimer assembly and HR-mediated genomic stabilization. Clinically, elevated SRSF11 expression is correlated with increased HR activity, radioresistance, and reduced survival in HCC patients. Notably, genetic disruption of the KAT2A-SRSF11 axis sensitizes HCC cells to radiation-induced apoptosis. Our findings establish succinylation as a novel regulatory mechanism linking alternative splicing to DNA repair fidelity in HCC, while proposing therapeutic targeting of this pathway to overcome radioresistance in advanced HCC.