ABSTRACT

Telomeres protect chromosome ends from nucleolytic degradation, uncontrolled recombination by DNA repair enzymes and checkpoint signaling, and they provide mechanisms for their maintenance by semiconservative DNA replication, telomerase and homologous recombination. The telomeric long noncoding RNA TERRA is transcribed from a large number of chromosome ends. TERRA has been implicated in modulating telomeric chromatin structure and checkpoint signaling, and in telomere maintenance by homology directed repair, and telomerase – when telomeres are damaged or very short. Recent work indicates that TERRA association with telomeres involves the formation of DNA:RNA hybrid structures that can be formed post transcription by the RAD51 DNA recombinase, which in turn may trigger homologous recombination between telomeric repeats and telomere elongation. In this review, we describe the mechanisms of TERRA recruitment to telomeres, R-loop formation and its regulation by shelterin proteins. We discuss the consequences of R-loop formation, with regard to telomere maintenance by DNA recombination and how this may impinge on telomere replication while counteracting telomere shortening in normal cells and in ALT cancer cells, which maintain telomeres in the absence of telomerase.

摘要

端粒保护染色体末端免受核酸降解、DNA 修复酶和检查点信号的失控重组，并且它们通过半保守的 DNA 复制、端粒酶和同源重组提供维持染色体末端的机制。端粒长非编码 RNA TERRA 由大量染色体末端转录而成。TERRA 参与调节端粒染色质结构和检查点信号传导，以及通过同源定向修复和端粒酶维持端粒 - 当端粒受损或非常短时。最近的研究表明，TERRA 与端粒的结合涉及 DNA：RNA 杂合结构的形成，这些结构可以通过 RAD51 DNA 重组酶在转录后形成，这反过来可能引发端粒重复和端粒延长之间的同源重组。在这篇综述中，我们描述了 TERRA 募集到端粒的机制、R 环的形成及其受庇护蛋白的调节。我们讨论了 R 环形成的后果，关于通过 DNA 重组维持端粒，以及这如何影响端粒复制，同时抵消正常细胞和 ALT 癌细胞中的端粒缩短，在没有端粒酶的情况下维持端粒。