Abstract：
Intrinsic or acquired chemoresistance represents a major obstacle in cancer treatment. Multiple mechanisms can contribute to cancer cells\' resistance to chemotherapy. Among them, an aberrantly strengthened DNA repair mechanism is responsible for a large proportion of drug resistance to alkylating agents and radiation therapy. In cancer cells, damping overactivated DNA repair system can overcome survival advantages conferred by chromosomal translocations or mutations and lead to cytostatic effects or cytotoxic. Therefore, selectively targeting DNA repair system in cancer cells holds promise for overcoming chemoresistance. In this study, we revealed that the endonuclease Flap Endonuclease 1 (FEN1), essential for DNA replication and repair, directly interacts with phosphatidylinositol 3-phosphate [PI(3)P], and FEN1-R378 is the primary PI(3)P-binding site. PI(3)P-binding deficient FEN1 mutant (FEN1-R378A) cells exhibited abnormal chromosomal structures and were hypersensitized to DNA damage. The PI(3)P-mediated FEN1 functionality was essential for repairing DNA damages caused by multiple mechanisms. Furthermore, VPS34, the major PI(3)P synthesizing enzyme, was negatively associated with patients\' survival in various cancer types, and VPS34 inhibitors significantly sensitized chemoresistant cancer cells to genotoxic agents. These findings open up an avenue for counteracting chemoresistance by targeting VPS34-PI(3)P-mediated DNA repair pathway, and call for assessing the efficacy of this strategy in patients suffering from chemoresistance-mediated cancer recurrence in clinical trials.
摘要：
内在或获得性化学抗性是癌症治疗中的主要障碍。多种机制可导致癌细胞对化疗的抗性。其中,异常增强的DNA修复机制导致了对烷化剂和放射治疗的大部分耐药性。在癌细胞中，阻尼过度激活的DNA修复系统可以克服染色体易位或突变赋予的生存优势，并导致细胞抑制作用或细胞毒性。因此,选择性靶向癌细胞中的DNA修复系统有望克服化学抗性。在这项研究中,我们揭示了核酸内切酶Flap核酸内切酶1（FEN1），对DNA复制和修复至关重要，直接与磷脂酰肌醇3-磷酸[PI(3)P]相互作用，FEN1-R378是主要的PI(3)P结合位点。PI（3）P结合缺陷型FEN1突变体（FEN1-R378A）细胞表现出异常的染色体结构，并对DNA损伤过敏。PI（3）P介导的FEN1功能对于修复由多种机制引起的DNA损伤至关重要。此外，VPS34，主要的PI(3)P合成酶，与各种癌症类型的患者生存率呈负相关，和VPS34抑制剂显着使化学抗性癌细胞对遗传毒性剂敏感。这些发现为通过靶向VPS34-PI（3）P介导的DNA修复途径来抵消化学耐药性开辟了一条途径，并呼吁在临床试验中评估该策略对化疗耐药介导的癌症复发患者的疗效。
