Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs
Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs
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DOI：
10.1016/s1097-2765(03)00196-5
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发表时间：
2003-05-01
期刊：
影响因子：
16
通讯作者：
Collins, K
中科院分区：
文献类型：
--
作者：
Fu, D;Collins, K
功能RNA根据来自前体表达上下文的线索进行处理。人端粒酶RNA(HTR)中存在H/ACA基序，提示端粒酶可能利用H/ACA小核仁RNA的生物发生途径。在这里，我们调查了HTR对加工、稳定性和功能的要求。我们发现，HTR的成熟不是依赖于转录上下文或前体序列的生物发生途径，而是需要H/ACA基序和HTR H/ACA结构域特有的额外基序的合作。这种端粒酶特异的htr元件在先天性角化不良中发生突变，与疾病相关的htr替换损害了RNA的积累。具有H/ACA结构域以外序列变化的疾病相关HTR变体不会影响RNA的加工或稳定性；相反，它们会造成催化缺陷。我们的结果揭示了HTR的生物发生与其他H/ACA基序RNA的不同，并表明了人类疾病中端粒酶抑制的不同机制。
Functional RNAs are processed according to cues from precursor expression context. The presence of an H/ACA motif within the human telomerase RNA (hTR) suggested that telomerase might utilize the biogenesis pathway of an H/ACA small nucleolar RNA. Here, we have investigated the requirements for processing, stability, and function of hTR. Instead of a biogenesis pathway dependent on transcription context or precursor sequence, we find that maturation of hTR requires cooperation of the H/ACA motif and an additional motif unique to the hTR H/ACA domain. This telomerase-specific hTR element is mutated in dyskeratosis congenita, and the disease-associated hTR substitution impairs RNA accumulation. Disease-associated hTR variants with sequence changes outside the H/ACA domain do not affect RNA processing or stability; they instead impose a catalytic defect. Our results reveal differences between the biogenesis of hTR and other H/ACA-motif RNAs and demonstrate distinct mechanisms of telomerase inhibition in human disease.