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U2AF65 assemblies drive sequence-specific splice site recognition.

ABSTRACT: The essential splicing factor U2AF65 is known to help anchoring U2 snRNP at the branch site. Its C-terminal UHM domain interacts with ULM motifs of SF3b155, an U2 snRNP protein. Here, we report a cooperative binding of U2AF65 and the related protein CAPER? to the multi-ULM domain of SF3b155. In addition, we show that the RS domain of U2AF65 drives a liquid-liquid phase separation that is amplified by intronic RNA with repeated pyrimidine tracts. In cells, knockdown of either U2AF65 or CAPER? improves the inclusion of cassette exons that are preceded by such repeated pyrimidine-rich motifs. These results support a model in which liquid-like assemblies of U2AF65 and CAPER? on repetitive pyrimidine-rich RNA sequences are driven by their RS domains, and facilitate the recruitment of the multi-ULM domain of SF3b155. We anticipate that posttranslational modifications and proteins recruited in dynamical U2AF65 and CAPER? condensates may further contribute to the complex mechanisms leading to specific splice site choice that occurs in cells.

SUBMITTER: Tari M 

PROVIDER: S-EPMC6681011 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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U2AF<sup>65</sup> assemblies drive sequence-specific splice site recognition.

Tari Manel M   Manceau Valérie V   de Matha Salone Jean J   Kobayashi Asaki A   Pastré David D   Maucuer Alexandre A  

EMBO reports 20190704 8

The essential splicing factor U2AF<sup>65</sup> is known to help anchoring U2 snRNP at the branch site. Its C-terminal UHM domain interacts with ULM motifs of SF3b155, an U2 snRNP protein. Here, we report a cooperative binding of U2AF<sup>65</sup> and the related protein CAPERα to the multi-ULM domain of SF3b155. In addition, we show that the RS domain of U2AF<sup>65</sup> drives a liquid-liquid phase separation that is amplified by intronic RNA with repeated pyrimidine tracts. In cells, knockdo  ...[more]

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