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

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 () and Caixia Guo ()
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Hui Fu: China National Center for Bioinformation
Min Huang: Chinese Academy of Sciences
Honglin Wu: University of Chinese Academy of Sciences
Hui Zheng: China National Center for Bioinformation
Yifei Gong: China National Center for Bioinformation
Lingyu Xing: Chinese Academy of Sciences
Juanjuan Gong: Chinese Academy of Sciences
Ruiyuan An: China National Center for Bioinformation
Qian Li: China National Center for Bioinformation
Xinyu Jie: University of Chinese Academy of Sciences
Xiaolu Ma: Chinese Academy of Sciences
Tie-Shan Tang: University of Chinese Academy of Sciences
Caixia Guo: China National Center for Bioinformation

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57599-8

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