染色体外DNA的起源及其对肿瘤发展的影响  

Origin of Extrachromosomal DNA and its Influence on Tumor Development

作　　者：陈宣亦 徐萌[1] CHEN Xuan-Yi;XU Meng(Guanghua School of Stomatology,Hospital of Stomatology,Guangdong Key Laboratory of Stomatology,Sun Yat-sen University,Guangzhou 510055,China)

机构地区：[1]中山大学光华口腔医学院·附属口腔医院,广东省口腔医学重点实验室,广州510055

出　　处：《中国生物化学与分子生物学报》2021年第9期1167-1173,共7页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.81602384);广东省自然科学基金-面上项目(No.2020A1515010529);国家留学基金(No.201906385068)资助。

摘　　要：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。Extrachromosomal DNA(ecDNA)is a class of circular DNA that is found off the chromosomes,either inside or outside the nucleus.ecDNA is abundant in cancer,and plays an important role during the tumor development.ecDNA contains multiple complete genes and regulatory elements that regulate transcription,including promoters and enhancers.It can replicate independently.However,the origin and mechanism of ecDNA is still unknown.Most scholars believe that DNA damage can elicit ecDNA production.The chromosomal fragments produced by DNA double-strand breaks are rearranged and circularized to form ecDNA via the non-homologous end-joining repair way.The chromatin on ecDNA is highly accessible and active.It works with oncogenes and co-amplify with enhancers to promote the transcription of oncogenes.Additionally,there are ultra-long-range chromatin contacts on ecDNA,which increases distant interaction.These features amplify the transcription of oncogenes and promote the development of tumors.Due to lack of centromeres,ecDNA has a non-equal segregation to daughter cells.Daughter cells,containing different copy numbers of ecDNA,can rapidly increase oncogene copy numbers,which drives the genome heterogeneity of the tumors.ecDNA-driven copy number regulation leads drug resistance and enables tumors to adapt quickly to the environment.Here we review the classification,origin of ecDNA and its role in tumorigenesis and development.We discuss the mechanisms of ecDNA promoting the transcription of oncogenes and leading to heterogeneity and drug resistance,aiming to provide new ideas on the diagnosis,treatment,and prognosis of tumors.

关 键 词：染色体外DNA 肿瘤 癌基因 异质性 耐药性 

分 类 号：R730.2[医药卫生—肿瘤]