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<p>DNA–RNA hybrids triggered by double-strand breaks (DSBs) are crucial intermediates during DSB repair, and their timely resolution requires numbers of RNA helicases, including DEAD box 1 (DDX1). However, how these helicases are recruited to DSB-induced hybrids in time remains largely unclear. Here, we revealed that squamous cell carcinoma antigen recognized by T cells 3 (SART3) promotes DDX1 binding to DNA–RNA hybrids at DSBs for optimal homologous recombination (HR) repair. SART3 itself associates with DNA–RNA hybrids and PAR chains and accumulates at DSBs in both PARylation- and DNA–RNA hybrids-dependent fashion. SART3 also associates with DDX1 and is necessary for DDX1 enrichment at DSBs. The defective SART3-DDX1 association observed in cells expressing the cancer-associated variant SART3-R836W impairs not only the accumulation of DDX1, but also hybrid removal and HR efficiency. Moreover, SART3 promotes DNA end resection through enhancing USP15-BARD1 association and BRCA1-BARD1 retention. Together, our study reveals an role of SART3 in DSB repair, rendering SART3 a promising target for cancer therapy.</p>

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SART3 promotes homologous recombination repair by stimulating DNA-RNA hybrids removal and DNA end resection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月6日

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  • Hui Fu,
  • Min Huang,
  • Honglin Wu,
  • Hui Zheng,
  • Yifei Gong,
  • Lingyu Xing,
  • Juanjuan Gong,
  • Ruiyuan An,
  • Qian Li,
  • Xinyu Jie,
  • Xiaolu Ma,
  • Tie-Shan Tang,
  • Caixia Guo

摘要

DNA–RNA hybrids triggered by double-strand breaks (DSBs) are crucial intermediates during DSB repair, and their timely resolution requires numbers of RNA helicases, including DEAD box 1 (DDX1). However, how these helicases are recruited to DSB-induced hybrids in time remains largely unclear. Here, we revealed that squamous cell carcinoma antigen recognized by T cells 3 (SART3) promotes DDX1 binding to DNA–RNA hybrids at DSBs for optimal homologous recombination (HR) repair. SART3 itself associates with DNA–RNA hybrids and PAR chains and accumulates at DSBs in both PARylation- and DNA–RNA hybrids-dependent fashion. SART3 also associates with DDX1 and is necessary for DDX1 enrichment at DSBs. The defective SART3-DDX1 association observed in cells expressing the cancer-associated variant SART3-R836W impairs not only the accumulation of DDX1, but also hybrid removal and HR efficiency. Moreover, SART3 promotes DNA end resection through enhancing USP15-BARD1 association and BRCA1-BARD1 retention. Together, our study reveals an role of SART3 in DSB repair, rendering SART3 a promising target for cancer therapy.