The U1 small nuclear ribonucleoprotein (snRNP) has an essential role in initiating spliceosome assembly, yet the mechanism underlying its synergy with other splicing regulators for efficient spliceosome assembly remains elusive. Here we identify zinc finger protein 207 (ZFP207) as a key regulator of U1 snRNP function that substantially promotes spliceosome assembly. Acute depletion of ZFP207 results in a series of molecular phenotypes indicative of U1 snRNP dysregulation. Mechanistically, the N-terminal zinc finger domains of ZFP207 directly bind to stem-loop 3 of U1 snRNA, while its C-terminal intrinsically disordered regions undergo phase separation to form biomolecular condensates with U1 snRNP. These condensates create a crowded molecular environment that increases the local concentration of splicing snRNPs and regulators, thereby accelerating the speed of spliceosome assembly by facilitating interactions between U1 snRNP and other snRNPs. Collectively, our study demonstrates the critical role of phase separation in ensuring effective U1 snRNP function and promoting efficient spliceosome assembly.
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In eukaryotes, the process of intron removal from nuclear pre-mRNA is performed by the spliceosome, a dynamic molecular machine composed of small nuclear ribonucleoproteins (snRNPs; U1, U2, U4, U5, and U6) and dozens of other protein splicing factors. The U6 snRNP contains the U6 snRNA and the proteins Prp24 and Lsm2-8 heteroheptamer. A key feature of the snRNP is a modified U6 snRNA 3' end, which in (yeast) contains a 3' phosphate.
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The U1 small nuclear ribonucleoprotein (snRNP) has an essential role in initiating spliceosome assembly, yet the mechanism underlying its synergy with other splicing regulators for efficient spliceosome assembly remains elusive. Here we identify zinc finger protein 207 (ZFP207) as a key regulator of U1 snRNP function that substantially promotes spliceosome assembly. Acute depletion of ZFP207 results in a series of molecular phenotypes indicative of U1 snRNP dysregulation.
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