Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point
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DOI：
10.1016/j.celrep.2015.09.053
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发表时间：
2015-11-03
期刊：
影响因子：
8.8
通讯作者：
Buonamici, Silvia
中科院分区：
文献类型：
--
作者：
Darman, Rachel B.;Seiler, Michael;Buonamici, Silvia
在几种人类癌症中观察到剪接体的复发突变，但其功能和治疗意义仍然难以捉摸。SF 3 B1是癌症中剪接体最常突变的组分，在RNA剪接中选择30个剪接位点（ss）期间参与分支点序列（BPS）的识别。在这里，我们报告说，常见的和肿瘤特异性剪接畸变诱导SF3B1突变，并建立异常的30 SS选择作为最常见的剪接缺陷。引人注目的是，突变体SF3B1利用的BPS不同于野生型SF3B1所使用的BPS，并且需要典型的30 ss以在第二步期间实现异常剪接。大约50%的异常剪接的mRNA进行无义介导的衰变，导致基因和蛋白质表达的下调。这些发现归因于SF3B1突变在癌症中的后果的功能意义。
Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 30 splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 30 ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wildtype SF3B1 and requires the canonical 30 ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.