Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first tim...Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first time the direct promotion of ecDNA in tumorigenesis and further uncovering how malignant cells acquire the uncontrolled function of the MDM2 and MYC.展开更多
文摘染色体外DNA(extrachromosomal DNA,ecDNA)是位于染色体外的环状DNA,存在于人类肿瘤细胞中,与人类肿瘤的发生发展相关。染色体外DNA含有多个完整的基因和调节转录的调节区,包括启动子和增强子,可以独立完成复制,其形成机制仍不明确。大多学者认为,DNA损伤会导致染色体外DNA的产生。由于DNA双链断裂(double-strand breaks,DSB)产生碎裂的染色体片段,通过非同源末端连接(non-homologous end joining,NHEJ)将这些片段重新排列,或环状连接而产生染色体外DNA。染色体外DNA的染色质具有高度可及性和活跃性;染色体外DNA上的增强子与癌基因共扩增,并对癌基因的转录起促进作用;染色体外DNA上可发生超远距离的染色质接触,从而对远距离的基因进行调控。以上因素促使染色体外DNA上的癌基因大量表达,最终促进癌症的发生发展。染色体外DNA缺乏着丝粒,使其不均等分离至子细胞,不仅使子细胞获得不同拷贝数量的染色体外DNA,还有利于获得更多染色体外DNA的细胞更快获得高拷贝数量的癌基因,导致肿瘤细胞的基因组异质性。同时,肿瘤通过染色体外DNA调节基因拷贝数,可使肿瘤逃避药物作用,从而使肿瘤产生耐药性,并能更好地适应环境的变化。本文主要综述染色体外DNA的分类、形成机制及其在肿瘤发生发展中的作用,讨论染色体外DNA促使肿瘤细胞高表达癌基因及其导致肿瘤细胞异质性和耐药性的机制,旨在为肿瘤的诊断、治疗及预后提供新思路。
基金supported by the National Natural Science Foundation of China(82201594 and 81502582)the Open project of State Key Laboratory of Animal Biotech Breeding(2025SKLAB6-13)the Construction Project of Liaoning Provincial Key Laboratory(2022JH13/10200026).
文摘Pradella et al.[1]recently published their latest research in Nature,reporting successful focal gene amplification in primary cells and organisms by engineering extrachromosomal DNA(ecDNA),confirming for the first time the direct promotion of ecDNA in tumorigenesis and further uncovering how malignant cells acquire the uncontrolled function of the MDM2 and MYC.
