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<p>Aberrant activation of DNA damage repair (DDR) pathways drives therapeutic resistance in cancer. Although Chromatin Assembly Factor 1 subunit A (CHAF1A) is well characterized for its role in chromatin assembly, its specific function in the DNA damage response has remained poorly defined. Here, we demonstrate that CHAF1A functions as a key regulator of DNA repair and radioresistance. Upon DNA double-strand breaks, CHAF1A is rapidly recruited to damage sites in an ATM-associated manner. Intriguingly, CHAF1A recruitment further enhances ATM phosphorylation and amplifies the DNA damage signal. Consequently, depletion of CHAF1A compromises the efficiency of both homologous recombination (HR) and non-homologous end joining (NHEJ). Mechanistically, CHAF1A governs repair pathway utilization in a cell cycle-dependent manner: during S phase, CHAF1A interacts with RAD51 in collaboration with PCNA, promoting the loading of RAD51 at DNA damage sites; whereas in non-S-phase cells, CHAF1A preferentially promotes the recruitment of KU70 to support NHEJ. Functionally, silencing CHAF1A markedly enhances tumor radiosensitivity, as robustly validated in cell-derived xenograft models and supported by proof-of-concept evidence from a patient-derived xenograft model. Collectively, our findings establish CHAF1A as a pivotal regulator of DNA damage repair in lung cancer models and position it as a promising therapeutic target for overcoming radioresistance.</p>

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CHAF1A promotes RAD51 loading and homologous recombination to drive tumor radioresistance

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Ruru Wang,
  • Yao Hou,
  • Jie Zhang,
  • Zhicheng Yao,
  • Xipeng Zhao,
  • Bin Chen,
  • Jie Zhang,
  • Shenglan Zhou,
  • Guoping Zhao,
  • Feng Xu

摘要

Aberrant activation of DNA damage repair (DDR) pathways drives therapeutic resistance in cancer. Although Chromatin Assembly Factor 1 subunit A (CHAF1A) is well characterized for its role in chromatin assembly, its specific function in the DNA damage response has remained poorly defined. Here, we demonstrate that CHAF1A functions as a key regulator of DNA repair and radioresistance. Upon DNA double-strand breaks, CHAF1A is rapidly recruited to damage sites in an ATM-associated manner. Intriguingly, CHAF1A recruitment further enhances ATM phosphorylation and amplifies the DNA damage signal. Consequently, depletion of CHAF1A compromises the efficiency of both homologous recombination (HR) and non-homologous end joining (NHEJ). Mechanistically, CHAF1A governs repair pathway utilization in a cell cycle-dependent manner: during S phase, CHAF1A interacts with RAD51 in collaboration with PCNA, promoting the loading of RAD51 at DNA damage sites; whereas in non-S-phase cells, CHAF1A preferentially promotes the recruitment of KU70 to support NHEJ. Functionally, silencing CHAF1A markedly enhances tumor radiosensitivity, as robustly validated in cell-derived xenograft models and supported by proof-of-concept evidence from a patient-derived xenograft model. Collectively, our findings establish CHAF1A as a pivotal regulator of DNA damage repair in lung cancer models and position it as a promising therapeutic target for overcoming radioresistance.