Department of Radiological Health Science, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.
Department of Radiation Biology and Health, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.
Int J Cancer. 2020 Jun 1;146(11):3098-3113. doi: 10.1002/ijc.32670. Epub 2019 Oct 6.
Ionizing radiation (IR) and cisplatin are frequently used cancer treatments, although the mechanisms of error-prone DNA repair-mediated genomic instability after anticancer treatment are not fully clarified yet. RECQL4 mutations mainly in the C-terminal region of the RECQL4 gene lead to the cancer-predisposing Rothmund-Thomson syndrome, but the function of RECQL4ΔC (C-terminus deleted) in error-prone DNA repair remains unclear. We established several RECQL4ΔC cell lines and found that RECQL4ΔC cancer cells, but not RECQL4ΔC nontumorigenic cells, exhibited IR/cisplatin hypersensitivity. Notably, RECQL4ΔC cancer cells presented increased RPA2/RAD52 foci after cancer treatments. RECQL4ΔC HCT116 cells exhibited increased error-prone single-strand annealing (SSA) activity and decreased alternative end-joining activities, suggesting that RECQL4 regulates the DNA repair pathway choice at double-strand breaks. RAD52 depletion by siRNA or RAD52 inhibitors (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside [AICAR], (-)-epigallocatechin [EGC]) or a RAD52-phenylalanine 79 aptamer significantly restrained the growth of RAD52-upregulated RECQL4ΔC HCT116 cells in vitro and in mouse xenografts. Remarkably, compared to single-agent cisplatin or EGC treatment, cisplatin followed by low-concentration EGC had a significant suppressive effect on RECQL4ΔC HCT116 cell growth in vivo. Together, the regimens targeting the RAD52-mediated SSA pathway after anticancer treatment may be applicable for cancer patients with RECQL4 gene mutations.
电离辐射（IR）和顺铂经常用于癌症治疗，尽管抗癌治疗后易错 DNA 修复介导的基因组不稳定性的机制尚未完全阐明。RECQL4 基因突变主要发生在 RECQL4 基因的 C 末端区域，导致易患癌症的 Rothmund-Thomson 综合征，但 RECQL4ΔC（C 端缺失）在易错 DNA 修复中的功能仍不清楚。我们建立了几个 RECQL4ΔC 细胞系，发现 RECQL4ΔC 癌细胞，而不是 RECQL4ΔC 非肿瘤细胞，表现出对 IR/顺铂的超敏反应。值得注意的是，RECQL4ΔC 癌细胞在癌症治疗后表现出增加的 RPA2/RAD52 焦点。RECQL4ΔC HCT116 细胞表现出增加的易错单链退火（SSA）活性和降低的替代末端连接活性，表明 RECQL4 调节双链断裂处的 DNA 修复途径选择。通过 siRNA 或 RAD52 抑制剂（5-氨基咪唑-4-甲酰胺-1-β-D-核糖呋喃苷[AICAR]，（-）-表没食子儿茶素[EGC]）或 RAD52-苯丙氨酸 79 适体耗尽 RAD52 可显著抑制体外和小鼠异种移植中 RAD52 上调的 RECQL4ΔC HCT116 细胞的生长。值得注意的是，与顺铂单药或 EGC 治疗相比，顺铂后用低浓度 EGC 对 RECQL4ΔC HCT116 细胞的生长具有显著的抑制作用。总之，针对抗癌治疗后 RAD52 介导的 SSA 途径的方案可能适用于具有 RECQL4 基因突变的癌症患者。
