人类端粒DNA的分子识别及其作用机制探讨

Molecular recognition of human telomeric DNA and the interaction mechanisms

核酸中富含短的G-碱基重复的序列可以形成一种复杂的高级结构,称为G-四链体(G-quadruplex).在基因组中,借助生物信息学发现这类富G序列广泛分布在基因的启动子区,特别是那些参与到复制中去的基因,例如癌基因.同时发现这类序列在mRNA的5′非翻译区(5′UTR)也广泛存在.这类序列在染色体末段端粒部位的存在及功能已得到充分阐明.已知端粒富含G-碱基序列,其3′末端以单链状态存在,这使得在一些小分子的选择性作用下端粒序列很容易形成G-四链体结构,进而破坏端粒结构,影响端粒酶活性.已知端粒酶在超过85%的肿瘤中过量表达,因此,端粒酶已经成为抗癌药物设计的特殊靶点,是目前本领域的研究热点之一.已发现系列配体通过有效抑制端粒酶而表现高的抗肿瘤活性.本文主要综述了近年来端粒G-四链体分子识别及其药物靶向的最新进展,并对其作用机理做了进一步的分析和探讨.

Nucleic acid sequences comprising repeats of short guanine tracts,can form complex higher order structures,termed quadruplexes.Occurrences of quadruplexes within the human genomes have been mapped by bioinformatics surveys,which have revealed over-representations in promoter regions,especially of genes involved in replication,such as oncogenes,as well as in 5＇UTR regions.Importantly,their occurrence has been most extensively characterised at the telomeric ends of eukaryotic chromosomes,whose DNA comprises such sequences,and where the extreme 3＇ends are single-stranded.This enables relatively facile formation of quadruplex arrangements under the influence of a quadruplex-selective small molecule to perturb telomere function and impede the action of telomerase,an enzyme overexpressed in ﹥85% of human cancer.Therefore,the highly distinctive nature of quadruplex topologies can act as novel therapeutic targets,using designed small molecules to stabilize a particular quadruplex.We survey here the basis of these approaches,together with current progress,and discuss their interaction mechanisms posed by telomeric quadruplex targeting.