人端粒i-motif:结构、识别和生物学功能

Human Telomeric i-motif:Its Structure,Recognition and Physiological Activity

人端粒i-motif是由人端粒末端富含胞嘧啶(cytosine,C)的核酸序列形成的特殊高级结构,在端粒重复序列RNA(telomeric repeat-containing RNA,TERRA)转录调控、端粒功能维持和端粒酶活性抑制等方面发挥重要作用。端粒i-motif与多种癌症的发生密切相关,是癌症治疗的一个新靶点。相对于核酸G-四链体等高级结构,端粒i-motif稳定性较差,且受溶液pH、离子状态和拥挤环境等的影响,其在近中性的生理环境下能否稳定形成,长久以来存在争议。采用体外筛选的小分子配体特异性识别并稳定端粒i-motif,为探究该结构的生物学功能以及以端粒为靶点的癌症治疗提供了新策略,是目前的研究热点。但相对于其他核酸高级结构,目前所报道的端粒i-motif特异性配体分子仍较为匮乏。因此,本文将简要介绍i-motif结构的发现历程及其结构特征,并着重对体外环境下人端粒i-motif稳定性的影响因素,以及目前已报道的端粒i-motif配体分子及其生物学功能和调控机制等进行综述。文章内容将为近生理条件下端粒i-motif的结构研究和以其为靶点的特异性配体筛选提供基础,同时也为人端粒相关的癌症机制探究和治疗策略开发等提供思路与方向。

The human telomeric i-motif(htel-iM)is a unique higher-order DNA structure formed by the cytosine-rich(C)sequences at the end of human telomeres.Studies have shown that htel-iM plays a significant role in the transcriptional regulation of telomeric repeat-containing RNA(TERRA),maintenance of telomere function and inhibition of telomerase activity.Thus,it is closely related to the development and progression of many cancers and is a promising new target for cancer treatment therapy.Compared to other nucleic acid higher-order structures such as G-quadruplexes,the stability of htel-iM is much weaker and affected by many factors like buffer pH,ionic conditions and molecular crowding environments.Therefore the existence of the iM structures in near neutral physiological conditions has been uncertain for a long time.Recently,using in-vitro screened small molecule ligands to selectively recognize and stabilize htel-iM provides a new strategy for the exploration of the biological relevance of htel-iM.Thus it has become a research hotspot to take telomere as a cancer treatment target.However,so far the reported small molecule ligands selectively targeting the htel-iM are far from sufficient compared with those targeting other higher-order nucleic acid structures.In this review,the discovery and the characteristic of the iM structures are briefly described,with an emphasis on the in-vitro affecting factors of the htel-iM structure,the reported htel-iM ligands and its biological relevance and regulation mechanisms,which will be helpful in further exploration of the htel-iM structure and ligand screening in near physiological conditions,and understanding the mechanism and developing novel therapeutic strategies for cancer treatment targeting the htel-iM structures.