The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

Lisa-Marie Appel, Vedran Franke, Johannes Benedum, Irina Grishkovskaya, Xué Strobl, Anton Polyansky, Gregor Ammann, Sebastian Platzer, Andrea Neudolt, Anna Wunder, Lena Walch, Stefanie Kaiser, Bojan Zagrovic, Kristina Djinovic-Carugo, Altuna Akalin and Dea Slade ()
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Lisa-Marie Appel: Medical University of Vienna
Vedran Franke: Max Delbrück Center
Johannes Benedum: Medical University of Vienna
Irina Grishkovskaya: Max Perutz Labs, University of Vienna, Vienna Biocenter
Xué Strobl: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Anton Polyansky: Max Perutz Labs, University of Vienna, Vienna Biocenter
Gregor Ammann: Goethe University Frankfurt
Sebastian Platzer: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Andrea Neudolt: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Anna Wunder: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Lena Walch: Medical University of Vienna, Max Perutz Labs, Vienna Biocenter
Stefanie Kaiser: Goethe University Frankfurt
Bojan Zagrovic: Max Perutz Labs, University of Vienna, Vienna Biocenter
Kristina Djinovic-Carugo: Max Perutz Labs, University of Vienna, Vienna Biocenter
Altuna Akalin: Max Delbrück Center
Dea Slade: Medical University of Vienna

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract The heptad repeats of the C-terminal domain (CTD) of RNA polymerase II (Pol II) are extensively modified throughout the transcription cycle. The CTD coordinates RNA synthesis and processing by recruiting transcription regulators as well as RNA capping, splicing and 3’end processing factors. The SPOC domain of PHF3 was recently identified as a CTD reader domain specifically binding to phosphorylated serine-2 residues in adjacent CTD repeats. Here, we establish the SPOC domains of the human proteins DIDO, SHARP (also known as SPEN) and RBM15 as phosphoserine binding modules that can act as CTD readers but also recognize other phosphorylated binding partners. We report the crystal structure of SHARP SPOC in complex with CTD and identify the molecular determinants for its specific binding to phosphorylated serine-5. PHF3 and DIDO SPOC domains preferentially interact with the Pol II elongation complex, while RBM15 and SHARP SPOC domains engage with writers and readers of m6A, the most abundant RNA modification. RBM15 positively regulates m6A levels and mRNA stability in a SPOC-dependent manner, while SHARP SPOC is essential for its localization to inactive X-chromosomes. Our findings suggest that the SPOC domain is a major interface between the transcription machinery and regulators of transcription and co-transcriptional processes.

Date: 2023
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DOI: 10.1038/s41467-023-35853-1

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