一个由 SNRPA1 与结构 RNA 元件相互作用调控的转移前剪接程序。
A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements.
机构信息
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
出版信息
Science. 2021 May 14;372(6543). doi: 10.1126/science.abc7531.
Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.
异常的选择性剪接是癌症的一个标志，但控制这一过程的潜在调控程序在很大程度上仍然未知。在这里，我们报告了一项系统的努力，旨在破译塑造乳腺癌转移过程中病理性剪接的 RNA 结构密码。我们发现了一个以前未知的结构剪接增强子，它在包含增加的剪接体中富集，这些剪接体在高转移性细胞中增加。我们表明，剪接体蛋白小核核糖核蛋白多肽 A'（SNRPA1）与这些增强子相互作用，促进剪接体的内含子包含。这种相互作用增强了转移性肺定植和癌细胞侵袭，部分原因是 SNRPA1 介导的剪接调节，这可以通过剪接调节形态发生素来抵消。我们的发现确立了 SNRPA1 作为乳腺癌中促进转移剪接增强子的非典型调节作用。
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