Formation and biological functions of unusual DNA/RNA structures formed by repeat sequences.

超过50%的大多数基因组是串联重复DNA序列，包括端粒、着丝粒、大、小和微卫星重复。重复DNA可以以不寻常的结构存在，而不是典型的右手B型双螺旋。重复序列在基因和染色体中的特定位置突出了它们的生物学重要性，特别是关于它们形成的不寻常结构。有证据表明，重复序列结构在基因调控、剪接、重组、表观遗传调控、重复序列长度突变等方面发挥作用。功能可能通过重复序列形成的生物物理结构来反映。重要的是，重复序列的长度极易改变，这些长度变化会显著影响其生物学功能。长度变化可能涉及不寻常的结构。我们的目标是了解不寻常的重复结构以及它们如何改变长度。 不寻常的重复结构的形成可能发生在DNA复制、修复、重组和转录过程中，当互补链变成未配对和单链时。滑动-DNA的形成是由于重复序列的失准。新转录的RNA可以形成不寻常的结构，如链内发夹和G-四链体。一些DNA序列可以形成转录诱导的RNA：DNA杂合体，称为R环。这些序列在基因和染色体中的特定位置凸显了它们的生物学重要性，特别是在它们形成的替代结构方面，这些结构极有可能具有功能作用。人们对这些功能知之甚少。大多数结构分析是在没有其配偶链的情况下对分离的DNA链进行的。此外，大多数研究使用短的合成寡重复序列，其显著短于其生物学对应部分，其在两条互补链存在下发生。这些研究产生的结果可能只是部分反映了生物学上可能发生的情况。要彻底了解这些重复序列形成的结构，以及相互作用和加工它们的蛋白质，必须包括使用互补链的生物学相关长度的研究。 重点放在广泛的重复（端粒，着丝粒，宏，迷你和微卫星重复），这是和不相关的疾病，我们将研究不寻常的结构的形成的重复;评估蛋白质-核酸相互作用，以及某些蛋白质在处理这些不寻常的结构重复长度变化的作用。这个建议集中在重复序列的基本分子和生物学方面。这个建议的结果将揭示自然和疾病相关的方面，这些重复。对本文研究的重复序列子集的疾病相关研究是其他赠款的重点。

More than 50% of most genomes are tandem repetitive DNA sequences, including telomeres, centromeres, macro-, mini- and microsatellite repeats. Repeat DNAs can exist in unusual structures beyond the canonical right-handed B-form double helix. The specific locations of repeats in genes and chromosomes highlight their biological importance, particularly with respect to the unusual structures they form. Evidence indicates that repeat structures play roles in gene regulation, splicing, recombination, epigenetic regulation, repeat length mutation, etc. Functions are likely to be reflected by the biophysical structures formed by the repeats. Importantly, the length of the repeat tracts are hyper-prone to change and these length changes can dramatically affect their biological function. Length changes likely involve unusual structures. Our goal is to understand unusual repeat structures and how they can change lengths. The formation of unusual repeat structures likely occurs during DNA replication, repair, recombination and transcription, when complementary strands become unpaired and single-stranded. Slipped-DNAs form by out-of-register misalignment of repeats. Newly transcribed RNAs can form unusual structures such as intra-strand hairpins and G-quadruplexes. Some DNA sequences can form transcriptionally induced RNA:DNA hybrids called R-loops. The specific locations of these sequences in genes and chromosomes highlight their biological importance, particularly with respect to the alternative structures they form, which are highly likely to have functional roles. These functions are poorly understood. Most structural analyses are performed on isolated DNA strands in the absence of their partner strand. Furthermore, most studies use short synthetic oligo repeats that are dramatically shorter than their biological counter-parts, which occur in the presence of both complementary strands. Such studies yield results that may only partially reflect what may occur biologically. A thorough understanding of the structures formed by these repeats, the proteins that interact and process them, must include studies using biologically relevant lengths of the complementary strands. With a focus upon a broad range of repeats (telomeres, centromeres, macro-, mini-, and micro-satellite repeats), that are and are not associated with disease, we will study the formation of unusual structures by the repeats; assess protein-nucleic acid interactions, as well as the roles of certain proteins in processing these unusual structures to repeat length changes. This proposal focuses upon the basic fundamental molecular and biological aspects of repeat sequences. The results of this proposal will shed light upon both the natural and disease related aspects of some of these repeats. Disease-related studies on a subset of the repeats studied herein are the focus of other grants.