CHAF1A促进RAD51装载和同源重组以驱动肿瘤放射抗性
CHAF1A promotes RAD51 loading and homologous recombination to drive tumor radioresistance.
作者
作者单位
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. gpz@ipp.ac.cn.
- High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. fengx118@mail.ustc.edu.cn.
摘要
中文
DNA损伤修复（DDR）通路的异常激活驱动癌症治疗耐药性。尽管染色质装配因子1亚基A（CHAF1A）在染色质装配中的作用已被充分表征，但其在DNA损伤反应中的特定功能仍不明确。在此，我们证明CHAF1A是DNA修复和放射抗性的关键调节因子。在DNA双链断裂时，CHAF1A以ATM相关方式迅速募集至损伤位点。有趣的是，CHAF1A募集进一步增强ATM磷酸化并放大DNA损伤信号。因此，CHAF1A缺失损害同源重组（HR）和非同源末端连接（NHEJ）的效率。机制上，CHAF1A以细胞周期依赖方式控制修复通路利用：在S期，CHAF1A与RAD51相互作用并与PCNA协作，促进RAD51在DNA损伤位点的装载；而在非S期细胞中，CHAF1A优先促进KU70的募集以支持NHEJ。功能上，沉默CHAF1A显著增强肿瘤放射敏感性，这在细胞来源异种移植模型中得到有力验证，并得到患者来源异种移植模型的概念验证证据支持。总之，我们的发现确立CHAF1A作为肺癌模型中DNA损伤修复的关键调节因子，并使其成为克服放射抗性的有前景的治疗靶点。
English
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.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 9.1
- 新锐分区
- 1区