Stress granules promote DNA damage repair through the G3BP1/NAT10/ATF3 axis to facilitate nasopharyngeal carcinoma progression

Aberrantly enhanced DNA damage repair contributes to therapy resistance and poor prognosis in nasopharyngeal carcinoma (NPC), but its regulatory mechanisms remain unclear. Stress granules (SGs) mediate tumor stress adaptation, yet their role in NPC DNA damage repair is unknown. Here, we show that SGs are significantly enriched in NPC cells under stress, and the SG core protein G3BP1 is highly expressed in NPC tissues (n = 111), correlating with metastasis and poor survival. Mechanistically, under stress, N-acetyltransferase 10 (NAT10)-catalyzed N4-acetylcytosine (ac4C) modification targets mRNAs of DNA repair genes (ATF3, LIG1, RNF168) to SGs, protecting them from degradation. Upon stress relief, these mRNAs are released for translation, enhancing DNA damage repair. The G3BP1/NAT10/ATF3 axis is critical for NPC DNA repair and metastasis, as blocking this axis (via G3BP1 depletion, NAT10 inhibitor remodelin, or ATF3 knockout) inhibits tumor growth and metastasis in vitro and in vivo. This study uncovers a novel ac4C-dependent mechanism by which SGs regulate DNA damage repair in NPC, identifying the G3BP1/NAT10/ATF3 axis as a potential therapeutic target for improving NPC prognosis.